US6114328A - Isoxazoline and isoxazole fibrogen receptor antagonists - Google Patents

Isoxazoline and isoxazole fibrogen receptor antagonists Download PDF

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US6114328A
US6114328A US08/978,295 US97829597A US6114328A US 6114328 A US6114328 A US 6114328A US 97829597 A US97829597 A US 97829597A US 6114328 A US6114328 A US 6114328A
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substituted
alkyl
aryl
alkoxy
hydroxy
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John Wityak
Chu-Biao Xue
Thais Motria Sielecki-Dzurdz
Richard Eric Olson
William Frank DeGrado
Gary Avonn Cain
Douglas Guy Batt
Donald Pinto
Munir Alwan Hussain
Shaker Ahmed Mousa
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Bristol Myers Squibb Pharma Co
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DuPont Merck Pharmaceutical Co
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    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to novel isoxazolines and isoxazoles which are useful as antagonists of the platelet glycoprotein IIb/IIIa fibrinogen receptor complex, to pharmaceutical compositions, including those for intranasal administration, containing such compounds, processes for preparing such compounds, and to methods of using these compounds, alone or in combination with other therapeutic agents, for the inhibition of platelet aggregation, as thrombolytics, and/or for the treatment of thromboembolic disorders.
  • Hemostasis is the normal physiological process in which bleeding from an injured blood vessel is arrested. It is a dynamic and complex process in which platelets play a key role. Within seconds of vessel injury, resting platelets become activated and are bound to the exposed matrix of the injured area by a phenomenon called platelet adhesion. Activated platelets also bind to each other in a process called platelet aggregation to form a platelet plug. The platelet plug can stop bleeding quickly, but it must be reinforced by fibrin for long-term effectiveness, until the vessel injury can be permanently repaired.
  • Thrombosis may be regarded as the pathological condition wherein improper activity of the hemostatic mechanism results in intravascular thrombus formation.
  • Activation of platelets and the resulting platelet aggregation and platelet factor secretion has been associated with a variety of pathophysiological conditions including cardiovascular and cerebrovascular thromboembolic disorders, for example, the thromboembolic disorders associated with unstable angina, myocardial infarction, transient ischemic attack, stroke, atherosclerosis and diabetes.
  • the contribution of platelets to these disease processes stems from their ability to form aggregates, or platelet thrombi, especially in the arterial wall following injury.
  • Platelets are activated by a wide variety of agonists resulting in platelet shape change, secretion of granular contents and aggregation. Aggregation of platelets serves to further focus clot formation by concentrating activated clotting factors at the site of injury.
  • endogenous agonists including adenosine diphosphate (ADP), serotonin, arachidonic acid, thrombin, and collagen, have been identified. Because of the involvement of several endogenous agonists in activating platelet function and aggregation, an inhibitor which acts against all agonists would represent a more efficacious antiplatelet agent than currently available antiplatelet drugs, which are agonist-specific.
  • Current antiplatelet drugs are effective against only one type of agonist; these include aspirin, which acts against arachidonic acid; ticlopidine, which acts against ADP; thromboxane A 2 synthetase inhibitors or receptor antagonists, which act against thromboxane A 2 ; and hirudin, which acts against thrombin.
  • GPIIb/IIIa platelet glycoprotein IIb/IIIa complex
  • GPIIb/IIIa membrane protein mediating platelet aggregation
  • GPIIb/IIIa does not bind soluble proteins on unstimulated platelets, but GPIIb/IIIa in activated platelets is known to bind four soluble adhesive proteins, namely fibrinogen, von Willebrand factor, fibronectin, and vitronectin.
  • fibrinogen The binding of fibrinogen and von Willebrand factor to GPIIb/IIIa causes platelets to aggregate.
  • the binding of fibrinogen is mediated in part by the Arg-Gly-Asp (RGD) recognition sequence which is common to the adhesive proteins that bind GPIIb/IIIa.
  • integrins In addition to GPIIb/IIIa, increasing numbers of other cell surface receptors have been identified which bind to extracellular matrix ligands or other cell adhesion ligands thereby mediating cell--cell and cell-matrix adhesion processes. These receptors belong to a gene superfamily called integrins and are composed of heterodimeric transmembrane glycoproteins containing ⁇ - and ⁇ -subunits. Integrin subfamilies contain a common ⁇ -subunit combined with different ⁇ -subunits to form adhesion receptors with unique specificity. The genes for eight distinct ⁇ -subunits have been cloned and sequenced to date.
  • ⁇ 4/ ⁇ 1 and ⁇ 5/ ⁇ 1 Two members of the ⁇ 1 subfamily, ⁇ 4/ ⁇ 1 and ⁇ 5/ ⁇ 1 have been implicated in various inflammatory processes.
  • Antibodies to ⁇ 4 prevent adhesion of lymphocytes to synovial endothelial cells in vitro, a process which may be of importance in rheumatoid arthritis (VanDinther-Janssen et al., J. Immunol., 1991, 147:4207). Additional studies with monoclonal anti- ⁇ 4 antibodies provide evidence that ⁇ 4/ ⁇ 1 may additionally have a role in allergy, asthma, and autoimmune disorders (Walsh et al., J. Immunol., 1991, 146:3419; Bochner et al., J. Exp.
  • Anti- ⁇ 4 antibodies also block the migration of leukocytes to the site of inflammation (Issedutz et al., J. Immunol., 1991, 147:4178).
  • the ⁇ v / ⁇ 3 heterodimer commonly referred to as the vitronectin receptor, is another member of the ⁇ 3 integrin subfamily and has been described in platelets, endothelial cells, melanoma, smooth muscle cells and on the surface of osteoclasts (Horton and Davies, J. Bone Min. Res. 1989, 4:803-808; Davies et al., J. Cell. Biol. 1989, 109:1817-1826; Horton, Int. J. Exp. Pathol., 1990, 71:741-759).
  • the vitronectin receptor binds a variety of RGD-containing adhesive proteins such as vitronectin, fibronectin, VWF, fibrinogen, osteopontin, bone sialo protein II and thrombospondin in a manner mediated by the RGD sequence.
  • RGD-containing adhesive proteins such as vitronectin, fibronectin, VWF, fibrinogen, osteopontin, bone sialo protein II and thrombospondin in a manner mediated by the RGD sequence.
  • Possible roles for ⁇ v / ⁇ 3 in angiogenesis, tumor progression, and neovascularization have been proposed (Brooks et al., Science, 1994, 264:569-571).
  • a key event in bone resorption is the adhesion of osteoclasts to the matrix of bone.
  • European Patent Application Publication Number 478363 relates to compounds having the general formula: ##STR1##
  • European Patent Application Publication Number 478328 relates to compounds having the general formula: ##STR2##
  • European Patent Application Publication Number 525629 (corresponds to Canadian Patent Application Publication Number 2,074,685) discloses compounds having the general formula: ##STR3##
  • PCT Patent Application 9307867 relates to compounds having the general formula: ##STR4##
  • European Patent Application Publication Number 4512831 relates to compounds having the general formula: ##STR5##
  • peptides and peptidomimetics exhibit very low oral bioavailability due to poor absorption and/or degradation in the GI tract and liver. Therefore, their use is limited to the parenteral route of administration.
  • Drugs with low bioavailability often have a large variability in pharmacological response due to an associated variability in drug delivery. This large variability in drug delivery may occur when the bioavailability is low because under those conditions, it takes only a small variation in bioavailability to give a large change in plasma drug concentration (W. K. Sietsema, The Absolute Oral Bioavailability of Selected Drug, International Journal of Clinical Pharmacology, Therapy and Toxicology, Vol. 27 No. 4-1989 (179-211)).
  • Peptides and peptidomimetics have also generally shown relatively low nasal bioavailability.
  • studies with the luteinizing hormone releasing hormone (LHRH) analog, nafarelin acetate showed that nasal bioavailability was only ⁇ 2% (S. T. Anik, G. McRae, C. Nerenberg, A. Worden, J. Foreman, J. Hwang, S. Kushinsky, R. E. Jones, and B. Vickery; J. Pharm., Sci. 73: 684-685 (1984)).
  • LHRH luteinizing hormone releasing hormone
  • the present invention provides novel nonpeptide compounds which bind to integrin receptors thereby altering cell-matrix and cell--cell adhesion processes.
  • the compounds of the present invention are useful for the treatment of inflammation, bone degradation, tumors, metastases, thrombosis, and cell aggregation-related conditions in a mammal.
  • One aspect of this invention provides novel compounds of Formula I (described below) which are useful as antagonists of the platelet glycoprotein IIb/IIIa complex.
  • the compounds of the present invention inhibit the binding of fibrinogen to platelet glycoprotein IIb/IIIa complex and inhibit the aggregation of platelets.
  • the present invention also includes pharmaceutical compositions containing such compounds of Formula I, and methods of using such compounds for the inhibition of platelet aggregation, as thrombolytics, and/or for the treatment of thromboembolic disorders.
  • the present invention also includes methods of treating cardiovascular disease, thrombosis or harmful platelet aggregation, reocclusion following thrombolysis, reperfusion injury, or restenosis by administering a compound of Formula I alone or in combination with one or more additional therapeutic agents selected from: anti-coagulants such as warfarin or heparin; anti-platelet agents such as aspirin, piroxicam or ticlopidine; thrombin inhibitors such as boroarginine derivatives, hirudin or argatroban; or thrombolytic agents such as tissue plasminogen activator, anistreplase, urokinase or streptokinase; or combinations thereof.
  • anti-coagulants such as warfarin or heparin
  • anti-platelet agents such as aspirin, piroxicam or ticlopidine
  • thrombin inhibitors such as boroarginine derivatives, hirudin or argatroban
  • thrombolytic agents such as tissue plasminogen activator
  • the present invention also provides novel compounds, pharmaceutical compositions and methods which may be used in the treatment or prevention of diseases which involve cell adhesion processes, including, but not limited to, rheumatoid arthritis, asthma, allergies, adult respiratory distress syndrome, graft versus host disease, organ transplantation, septic shock, psoriasis, eczema, contact dermatitis, osteoporosis, osteoarthritis, atherosclerosis, metastasis, wound healing, diabetic retinopathy, inflammatory bowel disease and other autoimmune diseases.
  • diseases which involve cell adhesion processes, including, but not limited to, rheumatoid arthritis, asthma, allergies, adult respiratory distress syndrome, graft versus host disease, organ transplantation, septic shock, psoriasis, eczema, contact dermatitis, osteoporosis, osteoarthritis, atherosclerosis, metastasis, wound healing, diabetic retinopathy, inflammatory bowel disease and other autoimmune diseases
  • kits comprising one or more containers containing pharmaceutical dosage units comprising a compound of Formula I, for the treatment of cell adhesion related disorders, including but not limited to thromboembolic disorders.
  • the present invention provides novel nonpeptide compounds of Formula I (described below) which bind to integrin receptors thereby altering cell-matrix and cell--cell adhesion processes.
  • the compounds of the present invention are useful for the treatment of inflammation, bone degradation, tumors, metastases, thrombosis, and cell aggregation-related conditions in a mammal.
  • One aspect of this invention provides compounds of Formula I (described below) which are useful as antagonists of the platelet glycoprotein IIb/IIIa complex.
  • the compounds of the present invention inhibit the binding of fibrinogen to the platelet glycoprotein IIb/IIIa complex and inhibit the aggregation of platelets.
  • the present invention also includes pharmaceutical compositions containing such compounds of Formula I, and methods of using such compounds for the inhibition of platelet aggregation, as thrombolytics, and/or for the treatment of thromboembolic disorders.
  • a first embodiment of this invention provides compounds of Formula I: ##STR7## or pharmaceutically acceptable salt or prodrug forms thereof wherein: b is a single or double bond;
  • R 1 is selected from R 2 (R 3 )N(CH 2 ) q Z--, R 2 (R 3 )N(R 2 N ⁇ )CN(R 2 ) (CH 2 ) q Z--, piperazinyl-(CH 2 ) q Z-- or ##STR8##
  • Z is selected from O, S, S( ⁇ O), or S( ⁇ O) 2 ;
  • R 2 and R 3 are independently selected from: H, C 1 -C 10 alkyl, C 2 -C 6 alkenyl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkylalkyl, C 6 -C 10 aryl, C 7 -C 11 arylalkyl, C 2 -C 7 alkylcarbonyl, C 6 -C 10 arylcarbonyl, C 2 -C 10 alkoxycarbonyl, C 4 -C 11 cycloalkoxycarbonyl, C 7 -C 11 bicycloalk
  • U is selected from:
  • V is selected from:
  • W is selected from:
  • X is selected from:
  • Y is selected from hydroxy, C 1 to C 10 alkyloxy, C 3 to C 11 cycloalkyloxy, C 6 to C 10 aryloxy, C 7 to C 11 aralkyloxy, C 3 to C 10 alkylcarbonyloxyalkyloxy, C 3 to C 10 alkoxycarbonyloxyalkyloxy, C 2 to C 10 alkoxycarbonylalkyloxy, C 5 to C 10 cycloalkylcarbonyloxyalkyloxy, C 5 to C 10 cycloalkaxycarbonyloxyalkyloxy, C 5 to C 10 cycloalkoxycarbonylalkyloxy, C 7 to C 11 aryloxycarbonylalkyloxy, C 8 to C 12 aryloxycarbonyloxyalkyloxy, C 8 to C 12 arylcarbonyloxyalkyloxyalkyloxy, C 8 to C 12 arylcarbonyloxyalkyloxyalkyloxy, C 8 to C 12 arylcarbonyloxyalky
  • R 4 and R 4b are independently selected from H, C 1 -C 10 alkyl, hydroxy, C 1 -C 10 alkoxy, nitro, C 1 -C 10 alkylcarbonyl, or --N(R 12 )R 13 ;
  • R 5 is selected from H, C 1 -C 8 alkyl, C 2 -C 6 alkenyl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkylmethyl, C 6 -C 10 aryl, C 7 -C 11 arylalkyl, or C 1 -C 10 alkyl substituted with 0-2 R 4b ;
  • R 5a is selected from hydrogen, hydroxy, C 1 to C 8 alkyl, C 2 to C 6 alkenyl, C 3 to C 11 cycloalkyl, C 4 to C 11 cycloalkylmethyl, C 1 -C 6 alkoxy, benzyloxy, C 6 to C 10 aryl, heteroaryl, heteroarylalkyl, C 7 to C 11 arylalkyl, adamantylmethyl or C 1 -C 10 alkyl substituted with 0-2 R 4b ;
  • R 5 and R 5a can be taken together to be 3-azabicyclononyl, 1-piperidinyl, 1-morpholinyl or 1-piperazinyl, each being optionally substituted with C 1 -C 6 alkyl, C 6 -C 10 aryl, heteroaryl, C 7 -C 11 arylalkyl, C 1 -C 6 alkylcarbonyl, C 3 -C 7 cycloalkylcarbonyl, C 1 -C 6 alkoxycarbonyl, C 7 -C 11 arylalkoxycarbonyl, C 1 -C 6 alkylsulfonyl or C 6 -C 10 arylsulfonyl;
  • R 5b is selected from C 1 -C 8 alkyl, C 2 -C 6 alkenyl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkylmethyl, C 6 -C 10 aryl, C 7 -C 11 arylalkyl, or C 1 -C 10 alkyl substituted with 0-2 R 4b ;
  • R 6 is selected from H, C 1 -C 10 alkyl, hydroxy, C 1 -C 10 alkoxy, nitro, C 1 -C 10 alkylcarbonyl, --N(R 12 )R 13 , cyano, halo, CF 3 , CHO, CO 2 R 5 , C( ⁇ O)R 5a , CONR 5 R 5a , OC( ⁇ O)R 5a , OC( ⁇ O)OR 5b , OR 5a , OC( ⁇ O)NR 5 R 5a , OCH 2 CO 2 R 5 , CO 2 CH 2 CO 2 R 5 , NR 5a C( ⁇ O)R 5a , NR 5a C( ⁇ O)OR 5b , NR 5a C( ⁇ O)NR 5 R 5a , NR 5a SO 2 NR 5 R 5a , NR 5a SO 2 R 5 , S(O) p R 5a , SO 2 NR 5 R 5a , C 2 -C 6 alkeny
  • C 6 to C 10 aryl optionally substituted with 1-3 groups selected from halogen, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, CF 3 , S(O) m Me, or --NMe 2 ;
  • arylalkyl C 7 to C 11 arylalkyl, said aryl being optionally substituted with 1-3 groups selected from halogen, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, CF 3 , S(O) m Me, or --NMe 2 ;
  • heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R 7 ;
  • R 6a is selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, CF 3 , NO 2 , or NR 12 R 13 ;
  • R 7 is selected from H, C 1 -C 10 alkyl, hydroxy, C 1 -C 10 alkoxy, nitro, C 1 -C 10 alkylcarbonyl, --N(R 12 )R 13 , cyano, halo, CF 3 , CHO, CO 2 R 5 , C( ⁇ O)R 5a , CONR 5 R 5a , OC( ⁇ O)R 5a , OC( ⁇ O)OR 5b , OR 5a , OC( ⁇ O)NR 5 R 5a , OCH 2 CO 2 R 5 , CO 2 CH 2 CO 2 R 5 , NO 2 , NR 5a C( ⁇ O)R 5a , NR 5a C( ⁇ O)OR 5b , NR 5a C( ⁇ O)NR 5 R 5a , NR 5a SO 2 NR 5 R 5a , NR 5a SO 2 R 5 , S(O) p R 5a , SO 2 NR 5 R 5a , C 2 -C
  • R 8 is selected from:
  • heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R 6 ;
  • R 12 and R 13 are independently H, C 1 -C 10 alkyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 alkylcarbonyl, C 1 -C 10 alkylsulfonyl, aryl(C 1 -C 10 alkyl)sulfonyl, arylsulfonyl, aryl, C 2 -C 6 alkenyl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkylalkyl, C 7 -C 11 arylalkyl, C 2 -C 7 alkylcarbonyl, C 7 -C 11 arylcarbonyl, C 2 -C 10 alkoxycarbonyl, C 4 -C 11 cycloalkoxycarbonyl, C 7 -C 11 bicycloalkoxycarbonyl, C 7 -C 11 aryloxycarbonyl, heteroarylcarbonyl, heteroarylalkylcarbonyl or aryl
  • R 14 is selected from H, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 1 -C 10 alkoxy, aryl, heteroaryl or C 1 -C 10 alkoxycarbonyl, CO 2 R 5 or --C( ⁇ O)N(R 5 )R 5a ;
  • R 15 is selected from:
  • heterocyclic ring containing 1-2 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-5 R 6 ;
  • n 0-4;
  • r 0-3;
  • n, q, and r are chosen such that the number of in-chain atoms between R 1 and Y is in the range of 8-18.
  • Preferred compounds of this first embodiment are those of Formula II (where W is a single bond (i.e., absent) and U is a single bond (i.e., absent)): ##STR10## wherein: R 1 is selected from R 2 HN(CH 2 ) q O--, R 2 HN(R 2 N ⁇ )CNH(CH 2 ) q O--, piperazinyl-(CH 2 ) q O--, or ##STR11## R 2 is selected from H, aryl(C 1 -C 10 alkoxy)carbonyl, C 1 -C 10 alkoxycarbonyl; and/or
  • R 8 is selected from H, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 3 -C 8 cycloalkyl, C 5 -C 6 cycloalkenyl, aryl, 5-6 membered heterocyclic ring containing 1-2 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated; and/or
  • R 6 and R 7 are selected from H, C 1 -C 10 alkyl, hydroxy, C 1 -C 10 alkoxy, nitro, C 1 -C 10 alkylcarbonyl, --N(R 12 )R 13 , cyano, or halo.
  • R 8 is selected from H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cycloalkyl, C 5 -C 6 cycloalkenyl, aryl, 5-6 membered heterocyclic ring containing 1-2 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated.
  • R 1 is ##STR13## V is phenylene or pyridylene; n is 1 or 2;
  • X is --(C 1 -C 2 )alkyl-substituted with 0-2 R 4
  • Y is selected from:
  • R 4 is --NR 12 R 13 ;
  • R 12 is H, C 1 -C 4 alkoxycarbonyl, C 1 -C 4 alkylcarbonyl, C 1 -C 4 alkylsulfonyl, arylalkylsulfonyl, arylsulfonyl, benzyl, benzoyl, phenoxycarbonyl, benzyloxycarbonyl, arylalkylsulfonyl, pyridylcarbonyl, or pyridylmethylcarbonyl; and
  • R 13 is H.
  • Specifically preferred compounds of this first embodiment are compounds, or pharmaceutically acceptable salt or prodrug forms thereof, selected from:
  • a second embodiment of this invention provides a compound of Formula I: ##STR14## or a pharmaceutically acceptable salt or prodrug form thereof wherein: b is a single or double bond;
  • R 1 is selected from R 2a (R 3 )N--, R 2 (R 3 )N(R 2 N ⁇ )C--, R 2a (R 3 )N(CH 2 ) q Z--, R 2 (R 3 )N(R 2 N ⁇ )C(CH 2 ) q Z--, R 2 (R 3 )N(R 2 N ⁇ )CN(R 2 )--, R 2 (R 3 )NC(O)--, R 2 (R 5 O)N(R 2 N ⁇ )C--, or R 2 (R 3 )N(R 5 ON ⁇ )C--; ##STR15##
  • Z is selected from a bond (i.e. is absent), O, S, S( ⁇ O), S( ⁇ O) 2 ;
  • R 2 and R 3 are independently selected from: H; C 1 -C 10 alkyl; C 3 -C 6 alkenyl; C 3 -C 11 cycloalkyl; C 4 -C 11 cycloalkylalkyl; C 6 -C 10 aryl optionally substituted with 0-3 groups selected from hydroxy, halogen, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, CF 3 , S(O) m CH 3 , --N(CH 3 ) 2 , C 1 -C 4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C 7 -C 11 arylalkyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, CF 3 , S(O) m CH 3 , --N(CH 3 ) 2 , C 1 -C 4 haloalkyl
  • R 2 and R 3 may be hydroxy
  • R 2a is R 2 or R 2 (R 3 )N(R 2 N ⁇ )C--;
  • U is selected from:
  • V is selected from:
  • Q is selected from:
  • W is selected from:
  • X is selected from:
  • Y is selected from hydroxy, C 1 to C 10 alkyloxy, C 3 to C 11 cycloalkyloxy, C 6 to C 10 aryloxy, C 7 to C 11 aralkyloxy, C 3 to C 10 alkylcarbonyloxyalkyloxy, C 3 to C 10 alkoxycarbonyloxyalkyloxy, C 2 to C 10 alkoxycarbonylalkyloxy, C 5 to C 10 cycloalkylcarbonyloxyalkyloxy, C 5 to C 10 cycloalkoxycarbonyloxyalkyloxy, C 5 to C 10 cycloalkoxycarbonylalkyloxy, C 7 to C 11 aryloxycarbonylalkyloxy, C 8 to C 12 aryloxycarbonyloxyalkyloxy, C 8 to C 12 arylcarbonyloxyalkyloxy, C 5 to C 10 alkoxyalkylcarbonyloxyalkyloxy, C 5 to C 10 (5-alkyl-1,3-dioxa-
  • R 4 is selected from H, C 1 -C 10 alkyl, C 1 -C 10 alkylcarbonyl, aryl, arylalkyl, cycloalkyl, or cycloalkylalkyl;
  • R 4 groups on adjacent carbons may join to form a bond (i.e. a carbon--carbon double or triple bond);
  • R 4a is selected from H, hydroxy, C 1 -C 10 alkoxy, nitro, N(R 5 )R 5a , --N(R 12 )R 13 , --N(R 16 )R 17 , C 1 -C 10 alkyl substituted with 0-3 R 6 , aryl substituted with 0-3 R 6 , heteroaryl substituted with 0-3 R 6 or C 1 -C 10 alkylcarbonyl;
  • R 4b is selected from H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, C 7 -C 14 bicycloalkyl, hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkylsulfinyl, C 1 -C 6 alkylsulfonyl, nitro, C 1 -C 6 alkylcarbonyl, C 6 -C 10 aryl, --N(R 12 )R 13 ; halo, CF 3 , CN, C 1 -C 6 alkoxycarbonyl, carboxy, piperidinyl, morpholinyl or pyridinyl;
  • R 5 is selected from H, C 1 -C 8 alkyl, C 3 -C 6 alkenyl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkylmethyl, C 6 -C 10 aryl, C 7 -C 11 arylalkyl, or C 1 -C 10 alkyl substituted with 0-2 R 4b ;
  • R 5a is selected from hydrogen, hydroxy, C 1 to C 8 alkyl, C 3 -C 6 alkenyl, C 3 to C 11 cycloalkyl, C 4 to C 11 cycloalkylmethyl, C 1 -C 6 alkoxy, benzyloxy, C 6 to C 10 aryl, heteroaryl, heteroarylalkyl, C 7 to C 11 arylalkyl, adamantylmethyl, or C 1 -C 10 alkyl substituted with 0-2 R 4b ;
  • R 5 and R 5a when both are substituents on the same nitrogen atom can be taken together with the nitrogen atom to which they are attached to form 3-azabicyclononyl, 1,2,3,4-tetrahydro-1-quinolinyl, 1,2,3,4-tetrahydro-2-isoquinolinyl, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl or 1-piperazinyl, each being optionally substituted with C 1 -C 6 alkyl, C 6 -C 10 aryl, heteroaryl, C 7 -C 11 arylalkyl, C 1 -C 6 alkylcarbonyl, C 3 -C 7 cycloalkylcarbonyl, C 1 -C 6 alkoxycarbonyl, C 7 -C 11 arylalkoxycarbonyl, C 1 -C 6 alkylsulf
  • R 5b is selected from C 1 -C 8 alkyl, C 2 -C 6 alkenyl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkylmethyl, C 6 -C 10 aryl, C 7 -C 11 arylalkyl, or C 1 -C 10 alkyl substituted with 0-2 R 4b ;
  • R 6 is selected from H, C 1 -C 10 alkyl, hydroxy, C 1 -C 10 alkoxy, nitro, C 1 -C 10 alkylcarbonyl, --N(R 12 )R 13 , cyano, halo, CF 3 , CHO, CO 2 R 5 , C( ⁇ O)R 5a , CONR 5 R 5a , OC( ⁇ O)R 5a , OC( ⁇ O)OR 5b , OR 5a , OC( ⁇ O)NR 5 R 5a , OCH 2 CO 2 R 5 , CO 2 CH 2 CO 2 R 5 , NO 2 , NR 5a C( ⁇ O)R 5a , NR 5a C( ⁇ O)OR 5b , NR 5a C( ⁇ O)NR 5 R 5a , NR 5a SO 2 NR 5 R 5a , NR 5a SO 2 R 5 , S(O) m R 5a , SO 2 NR 5 R 5a , SiMe 3
  • C 6 to C 10 aryl optionally substituted with 1-3 groups selected from halogen, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, CF 3 , S(O) m Me, or --NMe 2 ;
  • aryl being optionally substituted with 1-3 groups selected from halogen, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, CF 3 , S(O) m Me, or --NMe 2 ; methylenedioxy when R 6 is a substituent on aryl; or
  • heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R 7 ;
  • R 6a is selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, CF 3 , NO 2 , or NR 12 R 13 ;
  • R 7 is selected from H, C 1 -C 10 alkyl, hydroxy, C 1 -C 10 alkoxy, nitro, C 1 -C 10 alkylcarbonyl, --N(R 12 )R 13 , cyano, halo, CF 3 , CHO, CO 2 R 5 , C( ⁇ O)R 5a , CONR 5 R 5a , OC( ⁇ O)R 5a , OC( ⁇ O)OR 5b , OR 5a , OC( ⁇ O)NR 5 R 5a , OCH 2 CO 2 R 5 , CO 2 CH 2 CO 2 R 5 , NO 2 , NR 5a C( ⁇ O)R 5a , NR 5a C(O)OR 5b , NR 5a C( ⁇ O)NR 5 R 5a , NR 5a SO 2 NR 5 R 5a , NR 5a SO 2 R 5 , S(O) m R 5a , SO 2 NR 5 R 5a , C 2 to C 6 al
  • R 8 is selected from:
  • heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R 6 ;
  • R 12 and R 13 are independently H, C 1 -C 10 alkyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 alkylcarbonyl, C 1 -C 10 alkylsulfonyl, aryl(C 1 -C 10 alkyl)sulfonyl, arylsulfonyl, aryl(C 2 -C 10 alkenyl)sulfonyl, heteroarylsulfonyl, aryl, C 2 -C 6 alkenyl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkylalkyl, C 7 -C 11 arylalkyl, C 7 -C 11 arylcarbonyl, C 4 -C 11 cycloalkoxycarbonyl, C 7 -C 11 bicycloalkoxycarbonyl, C 7 -C 11 aryloxycarbonyl, heteroarylcarbonyl, heteroarylalkylcarbon
  • R 14 is selected from H, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 1 -C 10 alkoxy, aryl, heteroaryl or C 1 -C 10 alkoxycarbonyl, CO 2 R 5 or --C( ⁇ O)N(R 5 )R 5a ;
  • R 15 is selected from:
  • heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R 6 ;
  • R 16 is selected from:
  • R 17 is selected from: H, C 1 -C 10 alkyl, C 2 -C 6 alkenyl, C 3 -C 11 cycloalkyl, C 4 -C 15 cycloalkylalkyl, aryl, aryl(C 1 -C 10 alkyl)-;
  • R 18a is selected from:
  • heterocyclic ring system having 1-3 heteroatoms selected independently from O, S, and N, said heterocyclic ring being substituted with 0-4 R 19 ,
  • C 1 -C 6 alkyl substituted with a 5-10 membered heterocyclic ring system having 1-3 heteroatoms selected independently from O, S, and N, said heterocyclic ring being substituted with 0-4 R 19 ;
  • R 18b is selected from R 18a or H
  • R 19 is selected from H, halogen, CF 3 , CN, NO 2 , NR 12 R 13 , C 1 -C 8 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 11 cycloalkyl, C 4 -C 1 l cycloalkylalkyl, aryl, aryl(C 1 -C 6 alkyl)-, C 1 -C 6 alkoxy, or C 1 -C 4 alkoxycarbonyl.;
  • n 0-2;
  • n 0-4;
  • r 0-3;
  • n, q and r are chosen such that the number of atoms connecting R 1 and Y is in the range of 8-18.
  • Preferred compounds of this second embodiment are those compounds of Formula Ia: ##STR17## wherein: Z is selected from a bond (i.e. is absent), O, or S; and/or
  • R 2 is selected from H, aryl(C 1 -C 10 alkoxy)carbonyl, or C 1 -C 10 alkoxycarbonyl; and/or
  • W is --(CH 2 ) n C( ⁇ O)N(R 5a )--;
  • X is --(C(R 4 ) 2 ) n --C(R 4 )(R 8 )--CH(R 4 )--, with the proviso that when n is 0 or 1, then at least one of R 4a or R 8 is other than H or methyl; and/or
  • R 5 is selected from H or C 1 -C 10 alkyl substituted with 0-6 R 4b ;
  • R 6 is selected from H, C 1 -C 10 alkyl, hydroxy, C 1 -C 10 alkoxy, nitro, C 1 -C 10 alkylcarbonyl, --N(R 12 )R 13 , --NR 5 R 5a , CO 2 R 5 , S(O) m R 5 , OR 5 , cyano, halo;
  • C 6 to C 10 aryl optionally substituted with 1-3 groups selected from halogen, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, CF 3 , S(O) m Me, or --NMe 2 ;
  • arylalkyl C 7 to C 11 arylalkyl, said aryl being optionally substituted with 1-3 groups selected from halogen, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, CF 3 , S(O) m Me, or --NMe 2 ;
  • heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R 7 ;
  • R 7 is selected from selected from H, C 1 -C 10 alkyl, hydroxy, C 1 -C 10 alkoxy, nitro, C 1 -C 10 alkylcarbonyl, --N(R 12 )R 13 , cyano, or halo; and/or
  • R 8 is selected from:
  • heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R 6 ;
  • R 12 and R 13 are each independently selected from H, C 1 -C 10 alkyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 alkylcarbonyl, C 1 -C 10 alkylsulfonyl, aryl(C 1 -C 10 alkyl)sulfonyl, arylsulfonyl, aryl, heteroarylcarbonyl, or heteroarylalkylcarbonyl, wherein said aryls are optionally substituted with 0-3 substituents selected from the group consisting of: C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, CF 3 , and NO 2 .
  • W is --(CH 2 ) n C( ⁇ O)N(R 12 )--;
  • X is --C(R 4 )(R 8 )--C(R 4 ) 2 --.
  • R 1 is R 2 NHC( ⁇ NR 2 )--, R 2 NHC( ⁇ NR 2 )NH-- and V is phenylene or pyridylene, or
  • R 1 is ##STR19## and V is a single bond (i.e. V is absent); n is 1 or 2;
  • X is --CHR 8 CH 2 --
  • Y is selected from:
  • R 6 is selected from H, C 1 -C 4 alkyl, hydroxy, C 1 -C 4 alkoxy, nitro, C 1 -C 10 alkylcarbonyl, --N(R 12 )R 13 , --NR 5 R 5a , CO 2 R 5 , S(O) m R 5 , OR 5 , cyano, halo;
  • C 6 to C 10 aryl optionally substituted with 1-3 groups selected from halogen, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, CF 3 , S(O) m Me, or --NMe 2 ;
  • a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyridinyl, 3H-indolyl, carbazolyl, pyrrolidinyl, piperidinyl, indolinyl, isoxazolinyl or morpholinyl;
  • R 8 is selected from:
  • heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, isoxazolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyridinyl, 3H-indolyl, carbazolyl, pyrrolidinyl, piperidinyl, indolinyl, or morpholinyl, said heterocyclic ring being substituted with 0-2 R 6 ;
  • R 12 is selected from H, C 1 -C 6 alkyl, C 1 -C 4 alkoxycarbonyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkylsulfonyl, aryl(C 1 -C 4 alkyl)sulfonyl, arylsulfonyl, aryl, pyridylcarbonyl or pyridylmethylcarbonyl, wherein said aryls are optionally substituted with 0-3 substituents selected from the group consisting of: C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, CF 3 , and NO 2 ; and
  • R 13 is H.
  • Specifically preferred compounds of this second embodiment are compounds, or enantiomeric or diasteriomeric forms thereof, or mixtures of enantiomeric or diasteriomeric forms thereof, or a pharmaceutically acceptable salt or prodrug forms thereof, selected from:
  • said enantiomeric and diasteriomeric forms being selected from:
  • Also preferred compounds of the second embodiment are those compounds of Formula Ic: ##STR20## wherein: b is a single or double bond;
  • R 1 is selected from R 2a (R 3 )N--, R 2 (R 3 )N(R 2 N ⁇ )C--, R 2a (R 3 )N(CH 2 ) q Z--, R 2 (R 3 )N(R 2 N ⁇ )C(CH 2 ) q Z--, R 2 (R 3 )N(R 2 N ⁇ )CN(R 2 )--, R 2 (R 3 )NC(O)--, R 2 (R 5 O)N(R 2 N ⁇ )C--, or R 2 (R 3 )N(R 5 ON ⁇ )C--; ##STR21##
  • Z is selected from a bond (i.e.
  • R 2 and R 3 are independently selected from: H; C 1 -C 6 alkyl; C 7 -C 11 arylalkyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, CF 3 , S(O) m CH 3 , --N(CH 3 ) 2 , C 1 -C 4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C 1 -C 10 alkoxycarbonyl; aryl(C 1 -C 10 alkoxy)carbonyl where the aryl group is optionally substituted with 0-3 groups selected from hydroxy, halogen, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, CF 3 , S(O) m CH 3 , --N(CH 3 ) 2 , C 1 -C 4 haloalkyl, methylenedi
  • R 2a is R 2 or R 2 (R 3 )N(R 2 N ⁇ )C;
  • U is a single bond (i.e., U is not present)
  • V is selected from:
  • Q is not --O--, --S(O) m --, --N(R 12 )--, --C( ⁇ O)N(R 5a )--, --CH 2 O--, CH 2 N(R 12 )-- or --CH 2 S(O) m --;
  • W is selected from:
  • X is --C(R 4 ) 2 --CHR 4a --;
  • R 4 is selected from H, C 1 -C 10 alkyl, C 1 -C 10 alkylcarbonyl, aryl, arylalkyl, cycloalkyl, or cycloalkylalkyl;
  • R 4a is selected from hydroxy, C 1 -C 10 alkoxy, nitro, --N(R 5 )R 5a , --N(R 12 )R 13 , or --N(R 16 )R 17 , C 1 -C 10 alkyl substituted with 0-3 R 6 , aryl substituted with 0-3 R 6 , heteroaryl substituted with 0-3 R 6 , or C 1 -C 10 alkylcarbonyl;
  • R 4b is selected from H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkylsulfinyl, C 1 -C 6 alkylsulfonyl, nitro, C 1 -C 6 alkylcarbonyl, C 6 -C 10 aryl, --N(R 12 )R 13 , halo, CF 3 , CN, C 1 -C 6 alkoxycarbonyl, carboxy, piperidinyl, morpholinyl or pyridyl;
  • R 5 is selected from H or C 1 -C 10 alkyl substituted with 0-6 R 4b ;
  • R 5a is selected from hydrogen, hydroxy, C 1 to C 8 alkyl, C 2 to C 6 alkenyl, C 3 to C 11 cycloalkyl, C 4 to C 11 cycloalkylmethyl, C 1 -C 6 alkoxy, benzyloxy, C 6 to C 10 aryl, heteroaryl, heteroarylalkyl, C 7 to C 11 arylalkyl, or adamantylmethyl, C 1 -C 10 alkyl substituted with 0-2 R 4b ;
  • R 5 and R 5a can be taken together to be 3-azabicyclononyl, 1,2,3,4-tetrahydro-1-quinolinyl, 1,2,3,4-tetrahydro-2-isoquinolinyl, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl or 1-piperazinyl, each being optionally substituted with C 1 -C 6 alkyl, C 6 -C 10 aryl, heteroaryl, C 7 -C 11 arylalkyl, C 1 -C 6 alkylcarbonyl, C 3 -C 7 cycloalkylcarbonyl, C 1 -C 6 alkoxycarbonyl or C 7 -C 11 arylalkoxycarbonyl;
  • R 5b is selected from C 1 -C 8 alkyl, C 2 -C 6 alkenyl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkylmethyl, C 6 -C 10 aryl, C 7 -C 11 arylalkyl, or C 1 -C 10 alkyl substituted with 0-2 R 4b
  • Y is selected from hydroxy, C 1 to C 10 alkyloxy, C 3 to C 11 cycloalkyloxy, C 6 to C 10 aryloxy, C 7 to C 11 aralkyloxy, C 3 to C 10 alkylcarbonyloxyalkyloxy, C 3 to C 10 alkoxycarbonyloxyalkyloxy, C 2 to C 10 alkoxycarbonylalkyloxy, C 5 to C 10 cycloalkylcarbonyloxyalkyloxy, C 5 to C 10 cycloalkoxycarbonyloxyalkyloxy, C 5 to C 10 cycloalkoxycarbonylalkyloxy, C 7 to C 11 aryloxycarbonylalkyloxy, C 8 to C 12 aryloxycarbonyloxyalkyloxy, C 8 to C 12 arylcarbonyloxyalkyloxy, C 5 to C 10 alkoxyalkylcarbonyloxyalkyloxy, C 5 to C 10 (5-alkyl-1,3-dioxa-
  • R 6 and R 7 are each independently selected from H, C 1 -C 10 alkyl, hydroxy, C 1 -C 10 alkoxy, nitro, C 1 -C 10 alkylcarbonyl, --N(R 12 )R 13 , cyano, or halo;
  • R 12 and R 13 are each independently selected from H, C 1 -C 10 alkyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 alkylcarbonyl, C 1 -C 10 alkylsulfonyl, aryl(C 1 -C 10 alkyl)sulfonyl, arylsulfonyl, heteroarylcarbonyl, heteroarylalkylcarbonyl or aryl, wherein said aryls are optionally substituted with 0-3 substituents selected from the group consisting of: C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, CF 3 , and NO 2 ;
  • R 15 is selected from H, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 1 -C 10 alkoxy, aryl, heteroaryl or C 1 -C 10 alkoxycarbonyl, CO 2 R 5 or --C( ⁇ O)N(R 5 )R 5a ;
  • R 16 is selected from:
  • R 17 is selected from: H or C 1 -C 4 alkyl
  • R 18a is selected from:
  • heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, isoxazolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyrimidinyl, 3H-indolyl, carbazolyl, pyrrolidinyl, piperidinyl, indolinyl, or morpholinyl, said heterocyclic ring being substituted with 0-4 R 19 ;
  • R 18b is selected from R 18a or H
  • R 19 is selected from H, halogen, CF 3 , CN, NO 2 , NR 12 R 13 , C 1 -C 8 alkyl; C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkylalkyl, aryl, heteroaryl, aryl(C 1 -C 6 alkyl)-, or C 1 -C 4 alkoxycarbonyl;
  • n 0-4;
  • r 0-3;
  • n, q, and r are chosen such that the number of atoms between R 1 and Y is in the range of 8-17.
  • R 1 is selected from: R 2 (R 3 )N--, R 2 NH(R 2 N ⁇ )C--, R 2 NH(R 2 N ⁇ )CNH--, R 2 R 3 N(CH 2 ) p' Z--, R 2 NH(R 2 N ⁇ )CNH(CH 2 ) p" Z--, R 2 (R 3 )NC(O)--, R 2 (R 5 O)N(R 2 N ⁇ )C--, or R 2 (R 3 )N(R 5 ON ⁇ )C--; ##STR23## n is 0-1; p' is 4-6;
  • p" is 2-4;
  • Z is selected from a bond (i.e. is absent) or O;
  • V is a single bond (i.e., V is not present), -(phenyl)- or -(pyridyl)-;
  • W is selected from:
  • X is selected from:
  • Y is selected from:
  • R 16 is selected from:
  • R 17 is selected from H or C 1 -C 5 alkyl
  • R 18a is selected from:
  • heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, isoxazolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyrimidinyl, 3H-indolyl, carbazolyl, pyrrolidinyl, piperidinyl, indolinyl, or morpholinyl, said heterocyclic ring being substituted with 0-4 R 19 ;
  • R 1 is R 2 NH(R 2 N ⁇ )C-- or R 2 HN(R 2 N ⁇ )CNH-- and V is phenylene or pyridylene; or
  • R 1 is ##STR24## and V is a single bond (i.e. V is absent); n is 1 or 2;
  • R 18a is selected from:
  • heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, isoxazolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyrimidinyl, 3H-indolyl, carbazolyl, pyrrolidinyl, piperidinyl, indolinyl, isoxazolinyl or morpholinyl, said heterocyclic ring being substituted with 0-4 R 19 ;
  • Specifically preferred compounds of Formula Ib are compounds, or pharmaceutically acceptable salt forms thereof, selected from:
  • prodrug esters of the specifically preferred compounds of Formula Ib are also specifically preferred, said esters being chosen from the group consisting of:
  • a third embodiment of this invention provides a compound of Formula Id: ##STR25## or a pharmaceutically acceptable salt or prodrug form thereof wherein: R 1 is selected from is selected from R 2 (R 3 )N--, R 2 (R 3 )N(R 2 N ⁇ )C--, R 2 (R 3 )N(R 2 N ⁇ )CN(R 2 )--, R 2 (R 3 )N(CH 2 ) q Z--, R 2 (R 3 )N(R 2 N ⁇ )C(CH 2 ) q Z--, R 2 (R 3 )N(R 2 N ⁇ )CN(R 2 )(CH 2 ) q Z--, piperazinyl-(CH 2 ) q Z--, R 2 (R 3 )NC(O)--, R 2 (R 5 O)N(R 2 N ⁇ )C--, R 2 (R 3 )N(R 5 ON ⁇ )C--, ##STR26##
  • Z is selected from a bond (
  • R 2 and R 3 are independently selected from: H; C 1 -C 10 alkyl; C 3 -C 6 alkenyl; C 3 -C 11 cycloalkyl; C 4 -C 11 cycloalkylalkyl; C 6 -C 10 aryl optionally substituted with 0-3 groups selected from hydroxy, halogen, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, CF 3 , S(O) m CH 3 , --N(CH 3 ) 2 , C 1 -C 4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; , C 7 -C 11 arylalkyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, CF 3 , S(O) m CH 3 , --N(CH 3 ) 2 , C 1 -C 4 haloal
  • R 2 and R 3 may be hydroxy
  • U is selected from:
  • V is selected from:
  • X is selected from:
  • Y is selected from:
  • R 14 and W are attached to the same carbon and taken together to form a spiro-fused, 5-7 membered ring structure of the formula: ##STR27##
  • D, E, F and G are each independently selected from: C(R 6a ) 2 ;
  • heteroatom moiety selected from N, N(R 12 ), O, provided that no more than 2 of D, E, F and G are N, N(R 12 ), O, S, or C( ⁇ O);
  • the bond between D and E, E and F, or F and G in such spiro-fused ring may be a carbon-nitrogen double bond or a carbon--carbon double bond;
  • R 4 is selected from H, C 1 -C 10 alkyl, hydroxy, C 1 -C 10 alkoxy, nitro, C 1 -C 10 alkylcarbonyl, or --N(R 12 )R 13 ;
  • R 6 and R 7 are each independently selected from H, C 1 -C 10 alkyl, hydroxy, C 1 -C 10 alkoxy, nitro, C 1 -C 10 alkylcarbonyl, --N(R 12 )R 13 , cyano, halo, CF 3 , CHO, CO 2 R 5a , C( ⁇ O)R 5a , CONHR 5a , CON(R 12 ) 2 , OC( ⁇ O)R 5a , OC( ⁇ O)OR 5a , OR 5a , OC( ⁇ O)N(R 12 ) 2 , OCH 2 CO 2 R 5a , CO 2 CH 2 CO 2 R 5a , N(R 12 ) 2 , NO 2 , NR 12 C( ⁇ O)R 5a , NR 12 C( ⁇ O)OR 5a , NR 12 C( ⁇ O)N(R 12 ) 2 , NR 12 SO 2 N(R 12 ) 2 , NR 12 SO 2 R 5a , S
  • C 6 to C 10 aryl optionally substituted with 1-3 groups selected from halogen, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, CF 3 , S(O) m Me, or --NMe 2 ;
  • arylalkyl C 7 to C 11 arylalkyl, said aryl being optionally substituted with 1-3 groups selected from halogen, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, CF 3 , S(O) m Me, or --NMe 2 ;
  • R 6a is selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, CF 3 , NO 2 , or NR 12 R 13 ;
  • R 8 is selected from:
  • heterocyclic ring containing 1-2 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-5 R 6 ;
  • R 12 and R 13 are independently H, C 1 -C 10 alkyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 alkylcarbonyl, C 1 -C 10 alkylsulfonyl, aryl(C 1 -C 10 alkyl)sulfonyl, arylsulfonyl, aryl, C 2 -C 6 alkenyl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkylalkyl, C 7 -C 11 arylalkyl, C 2 -C 7 alkylcarbonyl, C 7 -C 11 arylcarbonyl, C 2 -C 10 alkoxycarbonyl, C 4 -C 11 cycloalkoxycarbonyl, C 7 -C 11 bicycloalkoxycarbonyl, C 7 -C 11 aryloxycarbonyl, heteroarylcarbonyl, heteroarylalkylcarbonyl or aryl
  • R 5 and R 5a are selected independently from H, C 1 to C 8 alkyl, C 2 to C 6 alkenyl, C 3 to C 11 cycloalkyl, C 4 to C 11 cycloalkylmethyl, C 6 to C 10 aryl, C 7 to C 11 arylalkyl, or C 1 -C 10 alkyl substituted with 0-8 R 4 ;
  • R 15 is selected from:
  • heterocyclic ring containing 1-2 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-5 R 6 ;
  • n 0-4;
  • p 1-3;
  • r 0-3;
  • n, p, q and r are chosen such that the number of atoms between R 1 and Y is in the range of 8-17.
  • Also preferred compounds of the second embodiment are those compounds of Formulae Ie or If: ##STR28## or enantiomeric or diasteriomeric forms thereof, or mixtures of enantiomeric or diasteriomeric forms thereof, or a pharmaceutically acceptable salt form thereof, wherein:
  • R 1 is R 2 (R 3 )N(R 2 N ⁇ )C--, R 2 (R 3 )N(R 2 N ⁇ )CN(R 2 )--, or R 2 (R 3 )N--;
  • R 2 and R 3 are independently selected from: H; C 1 -C 10 alkyl; C 3 -C 6 alkenyl; C 3 -C 11 cycloalkyl; C 4 -C 11 cycloalkylalkyl; C 6 -C 10 aryl optionally substituted with 0-3 groups selected from hydroxy, halogen, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, CF 3 , S(O) m CH 3 , --N(CH 3 ) 2 , C 1 -C 4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C 7 -C 11 arylalkyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, CF 3 , S(O) m CH 3 , --N(CH 3 ) 2 , C 1 -C 4 haloalkyl
  • R 2 and R 3 may be hydroxy
  • R 12 and R 13 are independently H, C 1 -C 10 alkyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 alkylcarbonyl, C 1 -C 10 alkylsulfonyl, aryl(C 1 -C 10 alkyl)sulfonyl, arylsulfonyl, aryl(C 2 -C 10 alkenyl)sulfonyl, heteroarylsulfonyl, aryl, C 2 -C 6 alkenyl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkylalkyl, C 7 -C 11 arylalkyl, C 7 -C 11 arylcarbonyl, C 4 -C 11 cycloalkoxycarbonyl, C 7 -C 11 bicycloalkoxycarbonyl, C 7 -C 11 aryloxycarbonyl, heteroarylcarbonyl, heteroarylalkylcarbon
  • R 16 is selected from:
  • R 18a is selected from: C 1 -C 8 alkyl substituted with 0-2 R 19 ,
  • heterocyclic ring system having 1-3 heteroatoms selected independently from O, S, and N, said heterocyclic ring being substituted with 0-4 R 19 ,
  • C 1 -C 6 alkyl substituted with a 5-10 membered heterocyclic ring system having 1-3 heteroatoms selected independently from O, S, and N, said heterocyclic ring being substituted with 0-4 R 19 ;
  • R 18b is selected from R 18a or H
  • R 19 is selected from H, halogen, CF 3 , CN, NO 2 , NR 12 R 13 , C 1 -C 8 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkylalkyl, aryl, aryl(C 1 -C 6 alkyl)-, C 1 -C 6 alkoxy, or C 1 -C 4 alkoxycarbonyl;
  • Y is selected from hydroxy, C 1 to C 10 alkyloxy, C 3 to C 11 cycloalkyloxy, C 6 to C 10 aryloxy, C 7 to C 11 aralkyloxy, C 3 to C 11 alkylcarbonyloxyalkyloxy, C 3 to C 10 alkoxycarbonyloxyalkyloxy, C 2 to C 10 alkoxycarbonylalkyloxy, C 5 to C 10 cycloalkylcarbonyloxyalkyloxy, C 5 to C 10 cycloalkoxycarbonyloxyalkyloxy, C 5 to C 10 cycloalkoxycarbonylalkyloxy, C 7 to C 11 aryloxycarbonylalkyloxy, C 8 to C 12 aryloxycarbonyloxyalkyloxy, C 8 to C 12 arylcarbonyloxyalkyloxy, C 5 to C 10 alkoxyalkylcarbonyloxyalkyloxy, C 5 to C 10 (5-alkyl-1,3-dioxa-
  • n 0-2;
  • n 0-2;
  • p 1-5.
  • Preferred compounds of this third embodiment are compounds of Formula III: ##STR30## wherein: R 1 is selected from R 2 HN--, H 2 N(R 2 N ⁇ )C--, H 2 N(R 2 N ⁇ )CNH--, R 2 HN(CH 2 ) q O--, H 2 N(R 2 N ⁇ )CNH(CH 2 ) q O--, piperazinyl-(CH 2 ) q O--, R 2 (R 3 )NC(O)--, R 2 (R 5 O)N(R 2 N ⁇ )C--, R 2 (R 3 )N(R 5 ON ⁇ )C--, ##STR31## R 2 and R 3 are selected from H; C 1 -C 6 alkyl; C 7 -C 11 arylalkyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, CF 3 , S(O) m CH 3
  • R 4 is selected from H, C 1 -C 10 alkyl, hydroxy, C 1 -C 10 alkoxy, nitro, C 1 -C 10 alkylcarbonyl, or --N(R 12 )R 13 ;
  • V is selected from:
  • X is selected from --(CH 2 ) n C( ⁇ O)N(R 12 )--, C 1 -C 7 alkylene substituted with 0-1 R 4 , C 2 -C 7 alkenylene, or C 2 -C 7 alkynylene;
  • Y is selected from:
  • Z is selected from O or CH 2 ;
  • D, E, F and G are each independently selected from:
  • heteroatom moiety selected from N, NH, O, provided that no more than 2 of D, E, F and G are N, NH, O or S;
  • the bond between D and E, E and F, or F and G in such spiro-fused ring may be a carbon-nitrogen double bond or a carbon--carbon double bond;
  • R 6 and R 7 are each independently selected from H, C 1 -C 10 alkyl, hydroxy, C 1 -C 10 alkoxy, nitro, C 1 -C 10 alkylcarbonyl, --N(R 12 )R 13 , cyano, or halo;
  • R 12 and R 13 are each independently selected from H, C 1 -C 10 alkyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 alkylcarbonyl, C 1 -C 10 alkylsulfonyl, aryl(C 1 -C 10 alkyl)sulfonyl, arylsulfonyl, heteroarylcarbonyl, heteroaryalkylcarbonyl or aryl;
  • n 0-4;
  • p 1-3;
  • r 0-3;
  • n, p, q and r are chosen such that the number of atoms between R 1 and Y is in the range of 8-17.
  • R 1 is R 2 NHC( ⁇ NR 2 )-- and V is phenyl or pyridyl or
  • R 1 is ##STR32## and V is a single bond (i.e. V is absent); n is 1 or 2;
  • X is C 1 -C 4 alkylene substituted with 0-1 R 4 ;
  • Y is selected from:
  • R 12 and R 13 are each independently selected from H, C 1 -C 6 alkyl, C 1 -C 4 alkoxycarbonyl, C 1 -C 4 alkylcarbonyl, C 1 -C 4 alkylsulfonyl, aryl(C 1 -C 4 alkyl)sulfonyl, arylsulfonyl, heteroarylcarbonyl, heteroaryalkylcarbonyl or aryl; and
  • R 13 is H.
  • Specifically preferred compounds of this third embodiment are compounds, or pharmaceutically acceptable salt or prodrug forms thereof, selected from:
  • a fourth embodiment of this invention provides compounds of Formula I: ##STR33## or pharmaceutically acceptable salt or prodrug forms thereof, wherein: R 1 is selected from:
  • Z is selected from O, S, S( ⁇ O), S( ⁇ O) 2 ;
  • R 2 and R 3 are independently selected from: H, C 1 -C 10 alkyl, C 2 -C 6 alkenyl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkylalkyl, C 6 -C 10 aryl, C 7 -C 11 arylalkyl, C 2 -C 7 alkylcarbonyl, C 7 -C 11 arylcarbonyl, C 2 -C 10 alkoxycarbonyl, C 4 -C 11 cycloalkoxy
  • U is optionally present and is selected from C 1 -C 7 alkylene, C 2 -C 7 alkenylene, C 2 -C 7 alkynylene, arylene, or pyridylene;
  • V is selected from:
  • W is -(aryl)-Z 1 -, wherein said aryl is substituted with 0-6 R 6 or R 7 ;
  • Z 1 is selected from a single bond (i.e., Z 1 is absent), --CH 2 --, O or S;
  • X is selected from:
  • Y is selected from hydroxy, C 1 to C 10 alkyloxy, C 3 to C 11 cycloalkyloxy, C 6 to C 10 aryloxy, C 7 to C 11 aralkyloxy, C 3 to C 10 alkylcarbonyloxyalkyloxy, C 3 to C 10 alkoxycarbonyloxyalkyloxy, C 2 to C 10 alkoxycarbonylalkyloxy, C 5 to C 10 cycloalkylcarbonyloxyalkyloxy, C 5 to C 10 cycloalkoxycarbonyloxyalkyloxy, C 5 to C 10 cycloalkoxycarbonylalkyloxy, C 7 to C 11 aryloxycarbonylalkyloxy, C 8 to C 12 aryloxycarbonyloxyalkyloxy, C 8 to C 12 arylcarbonyloxyalkyloxy, C 5 to C 10 alkoxyalkylcarbonyloxyalkyloxy, C 5 to C 10 (5-alkyl-1,3-dioxa-
  • R 4 is selected from H, C 1 -C 10 alkyl, hydroxy, C 1 -C 10 alkoxy, nitro, C 1 -C 10 alkylcarbonyl, or --N(R 12 )R 13 ;
  • R 6 and R 7 are each independently selected from H, C 1 -C 10 alkyl, hydroxy, C 1 -C 10 alkoxy, nitro, C 1 -C 10 alkylcarbonyl, --N(R 12 )R 13 , cyano, halo, CF 3 , CHO, CO 2 R 5a , C( ⁇ O)R 5a , CONHR 5a , CON(R 12 ) 2 , OC( ⁇ O)R 5a , OC( ⁇ O)OR 5a , OR 5a , OC( ⁇ O)N(R 12 ) 2 , OCH 2 CO 2 R 5a , CO 2 CH 2 CO 2 R 5a , N(R 12 ) 2 , NO 2 , NR 12 C ( ⁇ O) R 5a , NR 12 C( ⁇ O)OR 5a , NR 12 C( ⁇ O)N(R 12 ) 2 , NR 12 SO 2 N(R 12 ) 2 , NR 12 SO 2 R 5a , S
  • R 8 is selected from:
  • heterocyclic ring containing 1-2 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-5 R 6 ;
  • R 12 and R 13 are independently H, C 1 -C 10 alkyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 alkylcarbonyl, C 1 -C 10 alkylsulfonyl, aryl(C 1 -C 10 alkyl)sulfonyl, arylsulfonyl, aryl, C 2 -C 6 alkenyl, C 3 -C 11 cycloalkyl, C 4 -C 11 cycloalkylalkyl, C 7 -C 11 arylalkyl, C 2 -C 7 alkylcarbonyl, C 7 -C 11 arylcarbonyl, C 2 -C 10 alkoxycarbonyl, C 4 -C 11 cycloalkoxycarbonyl, C 7 -C 11 bicycloalkoxycarbonyl, C 7 -C 11 aryloxycarbonyl, heteroarylcarbonyl, heteroarylalkylcarbonyl or aryl
  • R 14 is selected from H, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 1 -C 10 alkoxy, aryl, heteroaryl or C 1 -C 10 alkoxycarbonyl, CO 2 R 5 or --C( ⁇ O)N(R 12 )R 13 ;
  • R 5 and R 5a are selected independently from H, C 1 to C 8 alkyl, C 2 to C 6 alkenyl, C 3 to C 11 cycloalkyl, C 4 to C 11 cycloalkylmethyl, C 6 to C 10 aryl, C 7 to C 11 arylalkyl, or C 1 -C 10 alkyl substituted with 0-8 R 4 ;
  • R 15 is selected from:
  • heterocyclic ring containing 1-2 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-5 R 6 ;
  • n 0-4;
  • r 0-3;
  • n, q, and r are chosen such that the number of atoms between R 1 and Y is about 8-17.
  • Preferred compounds of this fourth embodiment are those of Formula IV: ##STR35## wherein: R 1 is selected from R 2 HN(CH 2 ) q O--, R 2 HN(R 2 N ⁇ C)NH(CH 2 ) q O--, piperazinyl-(CH 2 ) q O--, or ##STR36## Z is O; R 2 is selected from H, aryl(C 1 -C 10 )alkoxycarbonyl, C 1 -C 10 alkoxycarbonyl;
  • V is selected from:
  • Z 1 is selected from a single bond (i.e., Z 1 is absent), O or S;
  • X is selected from:
  • Y selected from hydroxy, C 1 to C 10 alkyloxy, C 3 to C 11 cycloalkyloxy, C 6 to C 10 aryloxy, C 7 to C 11 aralkyloxy, C 3 to C 10 alkylcarbonyloxyalkyloxy, C 3 to C 10 alkoxycarbonyloxyalkyloxy, C 2 to C 10 alkoxycarbonylalkyloxy, C 5 to C 10 cycloalkylcarbonyloxyalkyloxy, C 5 to C 10 cycloalkoxycarbonyloxyalkyloxy, C 5 to C 10 cycloalkoxycarbonylalkyloxy, C 7 to C 11 aryloxycarbonylalkyloxy, C 8 to C 12 aryloxycarbonyloxyalkyloxy, C 8 to C 12 arylcarbonyloxyalkyloxy, C 5 to C 10 alkoxyalkylcarbonyloxyalkyloxy, C 5 to C 10 (5-alkyl-1,3-dioxa-cycl
  • R 4 is selected from H, C 1 -C 10 alkyl, hydroxy, C 1 -C 10 alkoxy, nitro, C 1 -C 10 alkylcarbonyl, or --N(R 12 )R 13 ;
  • R 6 and R 7 are selected from H, C 1 -C 10 alkyl, hydroxy, C 1 -C 10 alkoxy, nitro, C 1 -C 10 alkylcarbonyl, --N(R 12 )R 13 , cyano, or halo;
  • R 8 is selected from H, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 3 -C 8 cycloalkyl, C 5 -C 6 cycloalkenyl, aryl, 5-6 membered heterocyclic ring containing 1-2 N, O, or S, where said heterocyclic ring may be saturated, partially saturated, or fully unsaturated;
  • R 12 and R 13 are independently selected from H, C 1 -C 10 alkyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 alkylcarbonyl, C 1 -C 10 alkylsulfonyl, aryl(C 1 -C 10 alkyl)sulfonyl, arylsulfonyl, heteroarylcarbonyl, heteroarylalkylcarbonyl or aryl;
  • R 14 is selected from H, C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 1 -C 10 alkoxy, aryl, heteroaryl or C 1 -C 10 alkoxycarbonyl, CO 2 R 5 or --C( ⁇ O)N(R 12 )R 13 ;
  • R 5 is selected from H or C 1 -C 10 alkyl substituted with 0-6 R 4 ;
  • n 0-4;
  • n and q are chosen such that the number of atoms between R 1 and Y is in the range of 8-17.
  • R 1 is R 2 HN(CH 2 ) q O-- or ##STR37##
  • V is C 1 -C 3 alkylene;
  • Z 1 is a single bond (i.e. Z 1 is absent) or O;
  • X is C 1 -C 3 alkylene substituted with 0-1 R 4 ;
  • Y is selected from:
  • R 12 and R 13 are independently selected from H, C 1 -C 6 alkyl, C 1 -C 4 alkoxycarbonyl, C 1 -C 4 alkylcarbonyl, C 1 -C 6 alkylsulfonyl, aryl(C 1 -C 4 alkyl)sulfonyl, arylsulfonyl, heteroarylcarbonyl, heteroarylalkylcarbonyl or aryl;
  • R 13 is H.
  • Specifically preferred compounds of this fourth embodiment are compounds, or pharmaceutically acceptable salt or prodrug forms thereof, selected from:
  • a fifth embodiment of this invention provides a compound of Formula I: ##STR38## or a pharmaceutically acceptable salt or prodrug form thereof wherein: b is a single or double bond;
  • R 1 is selected from R 2a (R 3 )N--, R 2 (R 3 )N(R 2 N ⁇ )C--, R 2a (R 3 )N(CH 2 ) q Z--, R 2 (R 3 )N(R 2 N ⁇ )C(CH 2 ) q Z--, R 2 (R 3 )NC(O)--, R 2 (R 5 O)N(R 2 N ⁇ )C---, R 2 (R 3 )N(R 5 ON ⁇ )C--; ##STR39##
  • Z is selected from a bond (i.e. is absent), O, S, S( ⁇ O), S( ⁇ O) 2 ;
  • R 2 and R 3 are independently selected from: H; C 1 -C 10 alkyl; C 3 -C 6 alkenyl; C 3 -C 11 cycloalkyl; C 4 -C 11 cycloalkylalkyl; C 6 -C 10 aryl optionally substituted with 0-3 groups selected from hydroxy, halogen, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, CF 3 , S(O) m CH 3 , --N(CH 3 ) 2 , C 1 -C 4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C 7 -C 11 arylalkyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, CF 3 , S(O) m CH 3 , --N(CH 3 ) 2 , C 1 -C 4 haloalkyl
  • R 2 and R 3 may be hydroxy
  • R 2a is R 2 or R 2 (R 3 )N(R 2 N ⁇ )C;
  • U is selected from:
  • V is selected from:
  • W is selected from: ##STR40##
  • X is selected from: a single bond (i.e. X is absent) --(C(R 4 ) 2 ) n --C(R 4 )(R 8 )--C(R 4 )(R 4a )--, with the proviso that when n is 0 or 1, then at least one of R 4a or R 8 is other than H or methyl;
  • Y is selected from:

Abstract

This invention relates to novel isoxazolines and isoxazoles which are useful as antagonists of the platelet glycoprotein IIb/IIIa fibrinogen receptor complex or the vitronectin receptor, to pharmaceutical compositions containing such compounds, processes for preparing such compounds, and to methods of using these compounds, alone or in combination with other therapeutic agents, for the inhibition of platelet aggregation, as thrombolytics, and/or for the treatment of thromboembolic disorders.

Description

This is a division of application Ser. No. 08/455,436, filed May 31, 1995 now U.S. Pat. No. 5,849,736.
CROSS REFERENCE TO EARLIER FILED APPLICATION
This application is a continuation-in-part of U.S. patent application Ser. No. 08/337,929, filed Nov. 10, 1994 which is a continuation-in-part of U.S. patent application Ser. No. 08/232,961, filed Apr. 22, 1994 which is a continuation-in-part of U.S. patent application Ser. No. 08/157,598, filed Nov. 24, 1993. The disclosures of these earlier filed applications are hereby incorporated herein by reference.
FIELD OF THE INVENTION
This invention relates to novel isoxazolines and isoxazoles which are useful as antagonists of the platelet glycoprotein IIb/IIIa fibrinogen receptor complex, to pharmaceutical compositions, including those for intranasal administration, containing such compounds, processes for preparing such compounds, and to methods of using these compounds, alone or in combination with other therapeutic agents, for the inhibition of platelet aggregation, as thrombolytics, and/or for the treatment of thromboembolic disorders.
BACKGROUND OF THE INVENTION
Hemostasis is the normal physiological process in which bleeding from an injured blood vessel is arrested. It is a dynamic and complex process in which platelets play a key role. Within seconds of vessel injury, resting platelets become activated and are bound to the exposed matrix of the injured area by a phenomenon called platelet adhesion. Activated platelets also bind to each other in a process called platelet aggregation to form a platelet plug. The platelet plug can stop bleeding quickly, but it must be reinforced by fibrin for long-term effectiveness, until the vessel injury can be permanently repaired.
Thrombosis may be regarded as the pathological condition wherein improper activity of the hemostatic mechanism results in intravascular thrombus formation. Activation of platelets and the resulting platelet aggregation and platelet factor secretion has been associated with a variety of pathophysiological conditions including cardiovascular and cerebrovascular thromboembolic disorders, for example, the thromboembolic disorders associated with unstable angina, myocardial infarction, transient ischemic attack, stroke, atherosclerosis and diabetes. The contribution of platelets to these disease processes stems from their ability to form aggregates, or platelet thrombi, especially in the arterial wall following injury.
Platelets are activated by a wide variety of agonists resulting in platelet shape change, secretion of granular contents and aggregation. Aggregation of platelets serves to further focus clot formation by concentrating activated clotting factors at the site of injury. Several endogenous agonists including adenosine diphosphate (ADP), serotonin, arachidonic acid, thrombin, and collagen, have been identified. Because of the involvement of several endogenous agonists in activating platelet function and aggregation, an inhibitor which acts against all agonists would represent a more efficacious antiplatelet agent than currently available antiplatelet drugs, which are agonist-specific.
Current antiplatelet drugs are effective against only one type of agonist; these include aspirin, which acts against arachidonic acid; ticlopidine, which acts against ADP; thromboxane A2 synthetase inhibitors or receptor antagonists, which act against thromboxane A2 ; and hirudin, which acts against thrombin.
Recently, a common pathway for all known agonists has been identified, namely platelet glycoprotein IIb/IIIa complex (GPIIb/IIIa), which is the membrane protein mediating platelet aggregation. A recent review of GPIIb/IIIa is provided by Phillips et al. Cell (1991) 65: 359-362. The development of a GPIIb/IIIa antagonist represents a promising new approach for antiplatelet therapy.
GPIIb/IIIa does not bind soluble proteins on unstimulated platelets, but GPIIb/IIIa in activated platelets is known to bind four soluble adhesive proteins, namely fibrinogen, von Willebrand factor, fibronectin, and vitronectin. The binding of fibrinogen and von Willebrand factor to GPIIb/IIIa causes platelets to aggregate. The binding of fibrinogen is mediated in part by the Arg-Gly-Asp (RGD) recognition sequence which is common to the adhesive proteins that bind GPIIb/IIIa.
In addition to GPIIb/IIIa, increasing numbers of other cell surface receptors have been identified which bind to extracellular matrix ligands or other cell adhesion ligands thereby mediating cell--cell and cell-matrix adhesion processes. These receptors belong to a gene superfamily called integrins and are composed of heterodimeric transmembrane glycoproteins containing α- and β-subunits. Integrin subfamilies contain a common β-subunit combined with different α-subunits to form adhesion receptors with unique specificity. The genes for eight distinct β-subunits have been cloned and sequenced to date.
Two members of the β1 subfamily, α4/β1 and α5/β1 have been implicated in various inflammatory processes. Antibodies to α4 prevent adhesion of lymphocytes to synovial endothelial cells in vitro, a process which may be of importance in rheumatoid arthritis (VanDinther-Janssen et al., J. Immunol., 1991, 147:4207). Additional studies with monoclonal anti-α4 antibodies provide evidence that α4/β1 may additionally have a role in allergy, asthma, and autoimmune disorders (Walsh et al., J. Immunol., 1991, 146:3419; Bochner et al., J. Exp. Med., 1991 173:1553; Yednock et al., Nature, 1992, 356:63). Anti-α4 antibodies also block the migration of leukocytes to the site of inflammation (Issedutz et al., J. Immunol., 1991, 147:4178).
The αv /β3 heterodimer, commonly referred to as the vitronectin receptor, is another member of the β3 integrin subfamily and has been described in platelets, endothelial cells, melanoma, smooth muscle cells and on the surface of osteoclasts (Horton and Davies, J. Bone Min. Res. 1989, 4:803-808; Davies et al., J. Cell. Biol. 1989, 109:1817-1826; Horton, Int. J. Exp. Pathol., 1990, 71:741-759). Like GPIIb/IIIa, the vitronectin receptor binds a variety of RGD-containing adhesive proteins such as vitronectin, fibronectin, VWF, fibrinogen, osteopontin, bone sialo protein II and thrombospondin in a manner mediated by the RGD sequence. Possible roles for αv /β3 in angiogenesis, tumor progression, and neovascularization have been proposed (Brooks et al., Science, 1994, 264:569-571). A key event in bone resorption is the adhesion of osteoclasts to the matrix of bone. Studies with monoclonal antibodies have implicated the αv /β3 receptor in this process and suggest that a selective αv /β3 antagonist would have utility in blocking bone resorption (Horton et al., J. Bone Miner. Res., 1993, 8:239-247; Helfrich et al., J. Bone Miner. Res., 1992, 7:335-343).
Several RGD-peptidomimetic compounds have been reported which block fibrinogen binding and prevent the formation of platelet thrombi.
European Patent Application Publication Number 478363 relates to compounds having the general formula: ##STR1##
European Patent Application Publication Number 478328 relates to compounds having the general formula: ##STR2##
European Patent Application Publication Number 525629 (corresponds to Canadian Patent Application Publication Number 2,074,685) discloses compounds having the general formula: ##STR3##
PCT Patent Application 9307867 relates to compounds having the general formula: ##STR4##
European Patent Application Publication Number 4512831 relates to compounds having the general formula: ##STR5##
None of the above references teaches or suggests the compounds of the present invention which are described in detail below.
Most peptides and peptidomimetics exhibit very low oral bioavailability due to poor absorption and/or degradation in the GI tract and liver. Therefore, their use is limited to the parenteral route of administration.
Drugs with low bioavailability often have a large variability in pharmacological response due to an associated variability in drug delivery. This large variability in drug delivery may occur when the bioavailability is low because under those conditions, it takes only a small variation in bioavailability to give a large change in plasma drug concentration (W. K. Sietsema, The Absolute Oral Bioavailability of Selected Drug, International Journal of Clinical Pharmacology, Therapy and Toxicology, Vol. 27 No. 4-1989 (179-211)).
Peptides and peptidomimetics have also generally shown relatively low nasal bioavailability. For example, studies with the luteinizing hormone releasing hormone (LHRH) analog, nafarelin acetate, showed that nasal bioavailability was only ˜2% (S. T. Anik, G. McRae, C. Nerenberg, A. Worden, J. Foreman, J. Hwang, S. Kushinsky, R. E. Jones, and B. Vickery; J. Pharm., Sci. 73: 684-685 (1984)). Thus, the intranasal administration of peptides and peptidomimetics is generally not recommended.
SUMMARY OF THE INVENTION
The present invention provides novel nonpeptide compounds which bind to integrin receptors thereby altering cell-matrix and cell--cell adhesion processes. The compounds of the present invention are useful for the treatment of inflammation, bone degradation, tumors, metastases, thrombosis, and cell aggregation-related conditions in a mammal.
One aspect of this invention provides novel compounds of Formula I (described below) which are useful as antagonists of the platelet glycoprotein IIb/IIIa complex. The compounds of the present invention inhibit the binding of fibrinogen to platelet glycoprotein IIb/IIIa complex and inhibit the aggregation of platelets. The present invention also includes pharmaceutical compositions containing such compounds of Formula I, and methods of using such compounds for the inhibition of platelet aggregation, as thrombolytics, and/or for the treatment of thromboembolic disorders.
The present invention also includes methods of treating cardiovascular disease, thrombosis or harmful platelet aggregation, reocclusion following thrombolysis, reperfusion injury, or restenosis by administering a compound of Formula I alone or in combination with one or more additional therapeutic agents selected from: anti-coagulants such as warfarin or heparin; anti-platelet agents such as aspirin, piroxicam or ticlopidine; thrombin inhibitors such as boroarginine derivatives, hirudin or argatroban; or thrombolytic agents such as tissue plasminogen activator, anistreplase, urokinase or streptokinase; or combinations thereof.
The present invention also provides novel compounds, pharmaceutical compositions and methods which may be used in the treatment or prevention of diseases which involve cell adhesion processes, including, but not limited to, rheumatoid arthritis, asthma, allergies, adult respiratory distress syndrome, graft versus host disease, organ transplantation, septic shock, psoriasis, eczema, contact dermatitis, osteoporosis, osteoarthritis, atherosclerosis, metastasis, wound healing, diabetic retinopathy, inflammatory bowel disease and other autoimmune diseases.
Also included in the present invention are pharmaceutical kits comprising one or more containers containing pharmaceutical dosage units comprising a compound of Formula I, for the treatment of cell adhesion related disorders, including but not limited to thromboembolic disorders.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides novel nonpeptide compounds of Formula I (described below) which bind to integrin receptors thereby altering cell-matrix and cell--cell adhesion processes. The compounds of the present invention are useful for the treatment of inflammation, bone degradation, tumors, metastases, thrombosis, and cell aggregation-related conditions in a mammal.
One aspect of this invention provides compounds of Formula I (described below) which are useful as antagonists of the platelet glycoprotein IIb/IIIa complex. The compounds of the present invention inhibit the binding of fibrinogen to the platelet glycoprotein IIb/IIIa complex and inhibit the aggregation of platelets. The present invention also includes pharmaceutical compositions containing such compounds of Formula I, and methods of using such compounds for the inhibition of platelet aggregation, as thrombolytics, and/or for the treatment of thromboembolic disorders.
This invention relates to novel compounds of the Formula I: ##STR6## or a pharmaceutically acceptable salt or prodrug form thereof. [1] A first embodiment of this invention provides compounds of Formula I: ##STR7## or pharmaceutically acceptable salt or prodrug forms thereof wherein: b is a single or double bond;
R1 is selected from R2 (R3)N(CH2)q Z--, R2 (R3)N(R2 N═)CN(R2) (CH2)q Z--, piperazinyl-(CH2)q Z-- or ##STR8## Z is selected from O, S, S(═O), or S(═O)2 ; R2 and R3 are independently selected from: H, C1 -C10 alkyl, C2 -C6 alkenyl, C3 -C11 cycloalkyl, C4 -C11 cycloalkylalkyl, C6 -C10 aryl, C7 -C11 arylalkyl, C2 -C7 alkylcarbonyl, C6 -C10 arylcarbonyl, C2 -C10 alkoxycarbonyl, C4 -C11 cycloalkoxycarbonyl, C7 -C11 bicycloalkoxycarbonyl, C6 -C10 aryloxycarbonyl, aryl(C1 -C10 alkoxy)carbonyl, C1 -C6 alkylcarbonyloxy(C1 -C4 alkoxy)carbonyl, C6 -C10 arylcarbonyloxy(C1 -C4 alkoxy)carbonyl, C4 -C11 cycloalkylcarbonyloxy(C1 -C4 alkoxy) carbonyl;
U is selected from:
a single bond (i.e., U is not present),
--(C1 -C7 alkyl)-,
--(C2 -C7 alkenyl)-,
--(C2 -C7 alkynyl)-,
--(aryl)-substituted with 0-3 R6a, or
-(pyridyl)-substituted with 0-3 R6a ;
V is selected from:
a single bond (i.e., V is not present);
--(C1 -C7 alkyl)-, substituted with 0-3 groups independently selected from R6 or R7 ;
--(C2 -C7 alkenyl)-, substituted with 0-3 groups independently selected from R6 or R7 ;
---(C2 -C7 alkynyl)-, substituted with 0-2 groups independently selected from R6 or R7 ;
-(aryl)-, substituted with 0-2 groups independently selected from R6 or R7 ;
-(pyridyl)-, substituted with 0-2 groups independently selected from R6 or R7 ; or
-(pyridazinyl)-, substituted with 0-2 groups independently selected from R6 or R7 ;
W is selected from:
a single bond (i.e., W is not present),
--(C1 -C7 alkyl)-,
--(C2 -C7 alkenyl)-,
--(C2 -C7 alkynyl)-, or
--(C(R5)2)n C(═O)N(R5a)--;
X is selected from:
a single bond (i.e., X is not present);
--(C1 -C7 alkyl)-, substituted with 0-3 groups independently selected from R4, R8 or R14 ;
--(C2 -C7 alkenyl)-, substituted with 0-3 groups independently selected from R4, R8 or R14 ;
--(C2 -C7 alkynyl)-, substituted with 0-2 groups independently selected from R4, R8 or R14 ; or ##STR9## Y is selected from hydroxy, C1 to C10 alkyloxy, C3 to C11 cycloalkyloxy, C6 to C10 aryloxy, C7 to C11 aralkyloxy, C3 to C10 alkylcarbonyloxyalkyloxy, C3 to C10 alkoxycarbonyloxyalkyloxy, C2 to C10 alkoxycarbonylalkyloxy, C5 to C10 cycloalkylcarbonyloxyalkyloxy, C5 to C10 cycloalkaxycarbonyloxyalkyloxy, C5 to C10 cycloalkoxycarbonylalkyloxy, C7 to C11 aryloxycarbonylalkyloxy, C8 to C12 aryloxycarbonyloxyalkyloxy, C8 to C12 arylcarbonyloxyalkyloxy, C5 to C10 alkoxyalkylcarbonyloxyalkyloxy, C5 to C10 (5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, C10 to C14 (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy; or (R2)(R3)N-(C1 -C10 alkoxy)-;
R4 and R4b are independently selected from H, C1 -C10 alkyl, hydroxy, C1 -C10 alkoxy, nitro, C1 -C10 alkylcarbonyl, or --N(R12)R13 ;
R5 is selected from H, C1 -C8 alkyl, C2 -C6 alkenyl, C3 -C11 cycloalkyl, C4 -C11 cycloalkylmethyl, C6 -C10 aryl, C7 -C11 arylalkyl, or C1 -C10 alkyl substituted with 0-2 R4b ;
R5a is selected from hydrogen, hydroxy, C1 to C8 alkyl, C2 to C6 alkenyl, C3 to C11 cycloalkyl, C4 to C11 cycloalkylmethyl, C1 -C6 alkoxy, benzyloxy, C6 to C10 aryl, heteroaryl, heteroarylalkyl, C7 to C11 arylalkyl, adamantylmethyl or C1 -C10 alkyl substituted with 0-2 R4b ;
alternately, R5 and R5a can be taken together to be 3-azabicyclononyl, 1-piperidinyl, 1-morpholinyl or 1-piperazinyl, each being optionally substituted with C1 -C6 alkyl, C6 -C10 aryl, heteroaryl, C7 -C11 arylalkyl, C1 -C6 alkylcarbonyl, C3 -C7 cycloalkylcarbonyl, C1 -C6 alkoxycarbonyl, C7 -C11 arylalkoxycarbonyl, C1 -C6 alkylsulfonyl or C6 -C10 arylsulfonyl;
R5b is selected from C1 -C8 alkyl, C2 -C6 alkenyl, C3 -C11 cycloalkyl, C4 -C11 cycloalkylmethyl, C6 -C10 aryl, C7 -C11 arylalkyl, or C1 -C10 alkyl substituted with 0-2 R4b ;
R6 is selected from H, C1 -C10 alkyl, hydroxy, C1 -C10 alkoxy, nitro, C1 -C10 alkylcarbonyl, --N(R12)R13, cyano, halo, CF3, CHO, CO2 R5, C(═O)R5a, CONR5 R5a, OC(═O)R5a, OC(═O)OR5b, OR5a, OC(═O)NR5 R5a, OCH2 CO2 R5, CO2 CH2 CO2 R5, NR5a C(═O)R5a, NR5a C(═O)OR5b, NR5a C(═O)NR5 R5a, NR5a SO2 NR5 R5a, NR5a SO2 R5, S(O)p R5a, SO2 NR5 R5a, C2 -C6 alkenyl, C3 -C11 cycloalkyl, C4 -C11 cycloalkylmethyl;
C6 to C10 aryl optionally substituted with 1-3 groups selected from halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m Me, or --NMe2 ;
C7 to C11 arylalkyl, said aryl being optionally substituted with 1-3 groups selected from halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m Me, or --NMe2 ;
methylenedioxy when R6 is a substituent on aryl; or
a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R7 ;
R6a is selected from C1 -C4 alkyl, C1 -C4 alkoxy, halo, CF3, NO2, or NR12 R13 ;
R7 is selected from H, C1 -C10 alkyl, hydroxy, C1 -C10 alkoxy, nitro, C1 -C10 alkylcarbonyl, --N(R12)R13, cyano, halo, CF3, CHO, CO2 R5, C(═O)R5a, CONR5 R5a, OC(═O)R5a, OC(═O)OR5b, OR5a, OC(═O)NR5 R5a, OCH2 CO2 R5, CO2 CH2 CO2 R5, NO2, NR5a C(═O)R5a, NR5a C(═O)OR5b, NR5a C(═O)NR5 R5a, NR5a SO2 NR5 R5a, NR5a SO2 R5, S(O)p R5a, SO2 NR5 R5a, C2 -C6 alkenyl, C3 -C11 cycloalkyl, C4 -C11 cycloalkylmethyl, C6 -C10 aryl, or C7 -C11 arylalkyl;
R8 is selected from:
H;
R6 ;
C1 -C10 alkyl, substituted with 0-3 R6 ;
C2 -C10 alkenyl, substituted with 0-3 R6 ;
C2 -C10 alkynyl, substituted with 0-3 R6 ;
C3 -C8 cycloalkyl, substituted with 0-3 R6 ;
C5 -C6 cycloalkenyl, substituted with 0-2 R6 ;
aryl, substituted with 0-2 R6 ;
5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R6 ;
R12 and R13 are independently H, C1 -C10 alkyl, C1 -C10 alkoxycarbonyl, C1 -C10 alkylcarbonyl, C1 -C10 alkylsulfonyl, aryl(C1 -C10 alkyl)sulfonyl, arylsulfonyl, aryl, C2 -C6 alkenyl, C3 -C11 cycloalkyl, C4 -C11 cycloalkylalkyl, C7 -C11 arylalkyl, C2 -C7 alkylcarbonyl, C7 -C11 arylcarbonyl, C2 -C10 alkoxycarbonyl, C4 -C11 cycloalkoxycarbonyl, C7 -C11 bicycloalkoxycarbonyl, C7 -C11 aryloxycarbonyl, heteroarylcarbonyl, heteroarylalkylcarbonyl or aryl (C1 -C10 alkoxy) carbonyl;
R14 is selected from H, C1 -C10 alkyl, C2 -C10 alkenyl, C2 -C10 alkynyl, C1 -C10 alkoxy, aryl, heteroaryl or C1 -C10 alkoxycarbonyl, CO2 R5 or --C(═O)N(R5)R5a ;
R15 is selected from:
H;
R6 ;
C1 -C10 alkyl, substituted with 0-8 R6 ;
C2 -C10 alkenyl, substituted with 0-6 R6 ;
C1 -C10 alkoxy, substituted with 0-6 R6 ;
aryl, substituted with 0-5 R6 ;
5-6 membered heterocyclic ring containing 1-2 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-5 R6 ;
C1 -C10 alkoxycarbonyl substituted with 0-8 R6 ;
CO2 R5 ; or
--C(═O)N(R5)R5a ;
n is 0-4;
q is 2-7;
r is 0-3;
provided that when b is a double bond, only one of R14 or R15 is present;
provided that n, q, and r are chosen such that the number of in-chain atoms between R1 and Y is in the range of 8-18.
[2] Preferred compounds of this first embodiment are those of Formula II (where W is a single bond (i.e., absent) and U is a single bond (i.e., absent)): ##STR10## wherein: R1 is selected from R2 HN(CH2)q O--, R2 HN(R2 N═)CNH(CH2)q O--, piperazinyl-(CH2)q O--, or ##STR11## R2 is selected from H, aryl(C1 -C10 alkoxy)carbonyl, C1 -C10 alkoxycarbonyl; and/or
R8 is selected from H, C1 -C10 alkyl, C2 -C10 alkenyl, C3 -C8 cycloalkyl, C5 -C6 cycloalkenyl, aryl, 5-6 membered heterocyclic ring containing 1-2 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated; and/or
R6 and R7 are selected from H, C1 -C10 alkyl, hydroxy, C1 -C10 alkoxy, nitro, C1 -C10 alkylcarbonyl, --N(R12)R13, cyano, or halo.
[3] Further preferred compounds of this first embodiment are those of Formula II (where W is a bond/absent and U is a bond/absent): ##STR12## wherein: X is selected from:
a single bond (i.e., X is not present);
--(C1 -C7 alkyl)-, substituted with 0-2 groups independently selected from R4, R8 or R14 ;
--(C2 -C7 alkenyl)-, substituted with 0-2 groups independently selected from R4, R8 or R14 ;
--(C2 -C7 alkynyl)-, substituted with 0-2 groups independently selected from R4, R8 or R14 ; and/or
R8 is selected from H, C1 -C6 alkyl, C2 -C6 alkenyl, C3 -C8 cycloalkyl, C5 -C6 cycloalkenyl, aryl, 5-6 membered heterocyclic ring containing 1-2 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated.
[4] Further preferred compounds of this first embodiment are compounds of Formula II wherein:
R1 is ##STR13## V is phenylene or pyridylene; n is 1 or 2;
X is --(C1 -C2)alkyl-substituted with 0-2 R4
Y is selected from:
hydroxy;
C1 to C10 alkoxy;
methylcarbonyloxymethoxy-;
ethylcarbonyloxymethoxy-;
t-butylcarbonyloxymethoxy-;
cyclohexylcarbonyloxymethoxy-;
1-(methylcarbonyloxy)ethoxy-;
1-(ethylcarbonyloxy)ethoxy-;
1-(t-butylcarbonyloxy)ethoxy-;
1-(cyclohexylcarbonyloxy)ethoxy-;
i-propyloxycarbonyloxymethoxy-;
t-butyloxycarbonyloxymethoxy-;
1-(i-propyloxycarbonyloxy)ethoxy-;
1-(cyclohexyloxycarbonyloxy)ethoxy-;
1-(t-butyloxycarbonyloxy)ethoxy-;
dimethylaminoethoxy-;
diethylaminoethoxy-;
(5-methyl-1,3-dioxacyclopenten-2-on-4-yl)methoxy-;
(5-(t-butyl)-1,3-dioxacyclopenten-2-on-4-yl)methoxy-;
(1,3-dioxa-5-phenyl-cyclopenten-2-on-4-yl)methoxy-;
1-(2-(2-methoxypropyl)carbonyloxy)ethoxy-;
R4 is --NR12 R13 ;
R12 is H, C1 -C4 alkoxycarbonyl, C1 -C4 alkylcarbonyl, C1 -C4 alkylsulfonyl, arylalkylsulfonyl, arylsulfonyl, benzyl, benzoyl, phenoxycarbonyl, benzyloxycarbonyl, arylalkylsulfonyl, pyridylcarbonyl, or pyridylmethylcarbonyl; and
R13 is H.
[5] Specifically preferred compounds of this first embodiment are compounds, or pharmaceutically acceptable salt or prodrug forms thereof, selected from:
5(R,S)-3-[[4-(2-piperidin-4-yl)ethoxyphenyl]isoxazolin-5-yl]acetic acid;
5(R,S)-N-(butanesulfonyl)-L-{3-[4-(2-piperidin-4-yl)ethoxyphenyl]isoxazolin-5-yl}glycine;
5(R,S)-N-(α-toluenesulfonyl)-L-{3-[4-(2-piperidin-4-yl)ethoxyphenyl]isoxazolin-5-yl}glycine;
5(R,S)-N-[(benzyloxy)carbonyl]-L-{3-[4-(2-piperidin-4-yl)ethoxyphenyl]isoxazolin-5-yl}glycine;
5(R,S)-N-(pentanoyl)-L-{3-[4-(2-piperidin-4-yl)ethoxyphenyl]isoxazolin-5-yl}glycine;
5(R,S)-3-{[4-(piperidin-4-yl)methoxyphenyl]isoxazolin-5-yl}propanoic acid;
2(R,S)-5(R,S)-N-(butanesulfonyl)amino-{3-[4-(piperidin-4-yl)methoxyphenyl]isoxazolin-5-yl}propanoic acid;
2(R,S)-5(R,S)-N-(α-toluenesulfonyl)amino-{3-[4-(piperidin-4-yl)methoxyphenyl]isoxazolin-5-yl}propanoic acid;
2(R,S)-5(R,S)-N-[(benzyloxy)carbonyl]amino-{3-[4-(piperidin-4-yl)methoxyphenyl]isoxazolin-5-yl}propanoic acid;
2(R,S)-5(R,S)-N-(pentanoyl)amino-{3-[4-(piperidin-4-yl)methoxyphenyl]isoxazolin-5-yl}propanoic acid.
[6] A second embodiment of this invention provides a compound of Formula I: ##STR14## or a pharmaceutically acceptable salt or prodrug form thereof wherein: b is a single or double bond;
R1 is selected from R2a (R3)N--, R2 (R3)N(R2 N═)C--, R2a (R3)N(CH2)q Z--, R2 (R3)N(R2 N═)C(CH2)q Z--, R2 (R3)N(R2 N═)CN(R2)--, R2 (R3)NC(O)--, R2 (R5 O)N(R2 N═)C--, or R2 (R3)N(R5 ON═)C--; ##STR15## Z is selected from a bond (i.e. is absent), O, S, S(═O), S(═O)2 ;
R2 and R3 are independently selected from: H; C1 -C10 alkyl; C3 -C6 alkenyl; C3 -C11 cycloalkyl; C4 -C11 cycloalkylalkyl; C6 -C10 aryl optionally substituted with 0-3 groups selected from hydroxy, halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m CH3, --N(CH3)2, C1 -C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C7 -C11 arylalkyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m CH3, --N(CH3)2, C1 -C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C2 -C7 alkylcarbonyl; C7 -C11 arylcarbonyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m CH3, --N(CH3)2, C1 -C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C1 -C10 alkoxycarbonyl; C4 -C11 cycloalkoxycarbonyl; C7 -C11 bicycloalkoxycarbonyl; C7 -C11 aryloxycarbonyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m CH3, --N(CH3)2, C1 -C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; aryl(C1 -C10 alkoxy)carbonyl where the aryl group is optionally substituted with 0-3 groups selected from hydroxy, halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m CH3, --N(CH3)2, C1 -C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C1 -C6 alkylcarbonyloxy(C1 -C4 alkoxy)carbonyl; C6 -C10 arylcarbonyloxy(C1 -C4 alkoxy)carbonyl where the aryl group is optionally substituted with 0-3 groups selected from hydroxy, halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m CH3, --N(CH3)2, C1 -C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C4 -C11 cycloalkylcarbonyloxy(C1 -C4 alkoxy)carbonyl; heteroaryl optionally substituted with 0-2 groups selected from hydroxy, halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m CH3, --N(CH3)2, C1 -C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; or heteroaryl(C1 -C5)alkyl where the heteroaryl group is optionally substituted with 0-2 groups selected from hydroxy, halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m CH3, --N(CH3)2, C1 -C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl;
provided that only one of R2 and R3 may be hydroxy;
R2a is R2 or R2 (R3)N(R2 N═)C--;
U is selected from:
a single bond (i.e., U is not present),
--(C1 -C7 alkyl)-,
--(C2 -C7 alkenyl)-,
--(C2 -C7 alkynyl)-,
-(aryl)-substituted with 0-3 R6a, or
-(pyridyl)-substituted with 0-3 R6a ;
V is selected from:
a single bond (i.e., V is not present);
--(C1 -C7 alkyl)-, substituted with 0-3 groups independently selected from R6 or R7 ;
--(C2 -C7 alkenyl)-, substituted with 0-3 groups independently selected from R6 or R7 ;
--(C2 -C7 alkynyl)-, substituted with 0-3 groups independently selected from R6 or R7 ;
-(phenyl)-Q-, said phenyl substituted with 0-2 groups independently selected from R6 or R7 ;
-(pyridyl)-Q-, said pyridyl substituted with 0-2 groups independently selected from R6 or R7 ; or
-(pyridazinyl)-Q-, said pyridazinyl substituted with 0-2 groups independently selected from R6 or R7,
Q is selected from:
a single bond (i.e., Q is not present), --O--, --S(O)m --, --N(R12)--, --(CH2)m --, --C(═O)--, --N(R5a)C(═O)--, --C(═O)N(R5a)--, --CH2 O--, --OCH2 --, --CH2 N(R12)--, --N(R12)CH2 --, --CH2 C(═O)--, --C(═O)CH2 --, --CH2 S(O)m --, or --S(O)m CH2 --,
provided that when b is a single bond, and R.sup. --U--V-- is a substituent on C5 of the central 5-membered ring of Formula I, then Q is not --O--, --S(O)m --, --N(R12)--, --C(═O)N(R5a)--, --CH2 O--, CH2 N(R12)-- or --CH2 S(O)m --;
W is selected from:
--(C(R4)2)n C(═O)N(R5a)--, or
--C(═O)--N(R5a)--(C(R4)2)n --;
X is selected from:
a single bond (i.e. X is absent)
--(C(R4)2)n --C(R4)(R8)--C(R4)(R4a)--, with the proviso that when n is 0 or 1, then at least one of R4a or R8 is other than H or methyl;
Y is selected from hydroxy, C1 to C10 alkyloxy, C3 to C11 cycloalkyloxy, C6 to C10 aryloxy, C7 to C11 aralkyloxy, C3 to C10 alkylcarbonyloxyalkyloxy, C3 to C10 alkoxycarbonyloxyalkyloxy, C2 to C10 alkoxycarbonylalkyloxy, C5 to C10 cycloalkylcarbonyloxyalkyloxy, C5 to C10 cycloalkoxycarbonyloxyalkyloxy, C5 to C10 cycloalkoxycarbonylalkyloxy, C7 to C11 aryloxycarbonylalkyloxy, C8 to C12 aryloxycarbonyloxyalkyloxy, C8 to C12 arylcarbonyloxyalkyloxy, C5 to C10 alkoxyalkylcarbonyloxyalkyloxy, C5 to C10 (5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, C10 to C14 (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, (R2)(R3)N--(C1 -C10 alkoxy)-;
R4 is selected from H, C1 -C10 alkyl, C1 -C10 alkylcarbonyl, aryl, arylalkyl, cycloalkyl, or cycloalkylalkyl;
alternately, two R4 groups on adjacent carbons may join to form a bond (i.e. a carbon--carbon double or triple bond);
R4a is selected from H, hydroxy, C1 -C10 alkoxy, nitro, N(R5)R5a, --N(R12)R13, --N(R16)R17, C1 -C10 alkyl substituted with 0-3 R6, aryl substituted with 0-3 R6, heteroaryl substituted with 0-3 R6 or C1 -C10 alkylcarbonyl;
R4b is selected from H, C1 -C6 alkyl, C2 -C6 alkenyl, C2 -C6 alkynyl, C3 -C7 cycloalkyl, C7 -C14 bicycloalkyl, hydroxy, C1 -C6 alkoxy, C1 -C6 alkylthio, C1 -C6 alkylsulfinyl, C1 -C6 alkylsulfonyl, nitro, C1 -C6 alkylcarbonyl, C6 -C10 aryl, --N(R12)R13 ; halo, CF3, CN, C1 -C6 alkoxycarbonyl, carboxy, piperidinyl, morpholinyl or pyridinyl;
R5 is selected from H, C1 -C8 alkyl, C3 -C6 alkenyl, C3 -C11 cycloalkyl, C4 -C11 cycloalkylmethyl, C6 -C10 aryl, C7 -C11 arylalkyl, or C1 -C10 alkyl substituted with 0-2 R4b ;
R5a is selected from hydrogen, hydroxy, C1 to C8 alkyl, C3 -C6 alkenyl, C3 to C11 cycloalkyl, C4 to C11 cycloalkylmethyl, C1 -C6 alkoxy, benzyloxy, C6 to C10 aryl, heteroaryl, heteroarylalkyl, C7 to C11 arylalkyl, adamantylmethyl, or C1 -C10 alkyl substituted with 0-2 R4b ;
alternately, R5 and R5a when both are substituents on the same nitrogen atom (as in --NR5 R5a) can be taken together with the nitrogen atom to which they are attached to form 3-azabicyclononyl, 1,2,3,4-tetrahydro-1-quinolinyl, 1,2,3,4-tetrahydro-2-isoquinolinyl, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl or 1-piperazinyl, each being optionally substituted with C1 -C6 alkyl, C6 -C10 aryl, heteroaryl, C7 -C11 arylalkyl, C1 -C6 alkylcarbonyl, C3 -C7 cycloalkylcarbonyl, C1 -C6 alkoxycarbonyl, C7 -C11 arylalkoxycarbonyl, C1 -C6 alkylsulfonyl or C6 -C10 arylsulfonyl;
R5b is selected from C1 -C8 alkyl, C2 -C6 alkenyl, C3 -C11 cycloalkyl, C4 -C11 cycloalkylmethyl, C6 -C10 aryl, C7 -C11 arylalkyl, or C1 -C10 alkyl substituted with 0-2 R4b ;
R6 is selected from H, C1 -C10 alkyl, hydroxy, C1 -C10 alkoxy, nitro, C1 -C10 alkylcarbonyl, --N(R12)R13, cyano, halo, CF3, CHO, CO2 R5, C(═O)R5a, CONR5 R5a, OC(═O)R5a, OC(═O)OR5b, OR5a, OC(═O)NR5 R5a, OCH2 CO2 R5, CO2 CH2 CO2 R5, NO2, NR5a C(═O)R5a, NR5a C(═O)OR5b, NR5a C(═O)NR5 R5a, NR5a SO2 NR5 R5a, NR5a SO2 R5, S(O)m R5a, SO2 NR5 R5a, SiMe3, C2 to C6 alkenyl, C3 to C11 cycloalkyl, C4 to C11 cycloalkylmethyl;
C6 to C10 aryl optionally substituted with 1-3 groups selected from halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m Me, or --NMe2 ;
C7 to C11 arylalkyl, said aryl being optionally substituted with 1-3 groups selected from halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m Me, or --NMe2 ; methylenedioxy when R6 is a substituent on aryl; or
a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R7 ;
R6a is selected from C1 -C4 alkyl, C1 -C4 alkoxy, halo, CF3, NO2, or NR12 R13 ;
R7 is selected from H, C1 -C10 alkyl, hydroxy, C1 -C10 alkoxy, nitro, C1 -C10 alkylcarbonyl, --N(R12)R13, cyano, halo, CF3, CHO, CO2 R5, C(═O)R5a, CONR5 R5a, OC(═O)R5a, OC(═O)OR5b, OR5a, OC(═O)NR5 R5a, OCH2 CO2 R5, CO2 CH2 CO2 R5, NO2, NR5a C(═O)R5a, NR5a C(O)OR5b, NR5a C(═O)NR5 R5a, NR5a SO2 NR5 R5a, NR5a SO2 R5, S(O)m R5a, SO2 NR5 R5a, C2 to C6 alkenyl, C3 to C11 cycloalkyl, C4 to C11 cycloalkylmethyl, C6 to C10 aryl, or C7 to C11 arylalkyl;
R8 is selected from:
R6 ;
C1 -C10 alkyl, substituted with 0-3 R6 ;
C2 -C10 alkenyl, substituted with 0-3 R6 ;
C2 -C10 alkynyl, substituted with 0-3 R6 ;
C3 -C8 cycloalkyl, substituted with 0-3 R6 ;
C5 -C6 cycloalkenyl, substituted with 0-3 R6 ;
aryl, substituted with 0-3 R6 ;
5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R6 ;
R12 and R13 are independently H, C1 -C10 alkyl, C1 -C10 alkoxycarbonyl, C1 -C10 alkylcarbonyl, C1 -C10 alkylsulfonyl, aryl(C1 -C10 alkyl)sulfonyl, arylsulfonyl, aryl(C2 -C10 alkenyl)sulfonyl, heteroarylsulfonyl, aryl, C2 -C6 alkenyl, C3 -C11 cycloalkyl, C4 -C11 cycloalkylalkyl, C7 -C11 arylalkyl, C7 -C11 arylcarbonyl, C4 -C11 cycloalkoxycarbonyl, C7 -C11 bicycloalkoxycarbonyl, C7 -C11 aryloxycarbonyl, heteroarylcarbonyl, heteroarylalkylcarbonyl, or aryl(C1 -C10 alkoxy)carbonyl, wherein said aryls are optionally substituted with 0-3 substituents selected from the group consisting of: C1 -C4 alkyl, C1 -C4 alkoxy, halo, CF3, and NO2 ;
R14 is selected from H, C1 -C10 alkyl, C2 -C10 alkenyl, C2 -C10 alkynyl, C1 -C10 alkoxy, aryl, heteroaryl or C1 -C10 alkoxycarbonyl, CO2 R5 or --C(═O)N(R5)R5a ;
R15 is selected from:
H; R6 ; --CO2 R5 ; --C(═O)N(R5)R5a ;
C1 -C10 alkoxycarbonyl substituted with 0-2 R6 ;
C1 -C10 alkyl, substituted with 0-3 R6 ;
C2 -C10 alkenyl, substituted with 0-3 R6 ;
C1 -C10 alkoxy, substituted with 0-3 R6 ;
aryl, substituted with 0-3 R6 ; or
5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R6 ;
provided that when b is a double bond, only one of R14 or R15 is present;
R16 is selected from:
--C(═O)--O--R18a,
--C(═O)--R18b,
--C(═O)N(R18b)2,
--C(═O)NHSO2 R18a,
--C(═O)NHC(═O)R18b,
--C(═O)NHC(═O)OR18a,
--C(═O)NHSO2 NHR18b,
--C(═S)--NH--R18b,
--NH--C(═O)--O--R18a,
--NH--C(═O)--R18b,
--NH--C(═O)--NH--R18b,
--SO2 --O--R18a,
--SO2 --R18a,
--SO2 --N(18b)2,
--SO2 --NHC(═O)O18b,
--P(═S)(OR18a)2,
--P(═O)(OR18a)2,
--P(═S)(R18a)2,
--P(═O)(R18a)2, or ##STR16## R17 is selected from: H, C1 -C10 alkyl, C2 -C6 alkenyl, C3 -C11 cycloalkyl, C4 -C15 cycloalkylalkyl, aryl, aryl(C1 -C10 alkyl)-;
R18a is selected from:
C1 -C8 alkyl substituted with 0-2 R19, C2 -C8 alkenyl substituted with 0-2 R19, C2 -C8 alkynyl substituted with 0-2 R19, C3 -C8 cycloalkyl substituted with 0-2 R19, aryl substituted with 0-4 R19, aryl(C1 -C6 alkyl)-substituted with 0-4 R19,
a 5-10 membered heterocyclic ring system having 1-3 heteroatoms selected independently from O, S, and N, said heterocyclic ring being substituted with 0-4 R19,
C1 -C6 alkyl substituted with a 5-10 membered heterocyclic ring system having 1-3 heteroatoms selected independently from O, S, and N, said heterocyclic ring being substituted with 0-4 R19 ;
R18b is selected from R18a or H;
R19 is selected from H, halogen, CF3, CN, NO2, NR12 R13, C1 -C8 alkyl, C2 -C6 alkenyl, C2 -C6 alkynyl, C3 -C11 cycloalkyl, C4 -C1 l cycloalkylalkyl, aryl, aryl(C1 -C6 alkyl)-, C1 -C6 alkoxy, or C1 -C4 alkoxycarbonyl.;
m is 0-2;
n is 0-4;
q is 1-7;
r is 0-3;
provided that n, q and r are chosen such that the number of atoms connecting R1 and Y is in the range of 8-18.
[7] Preferred compounds of this second embodiment are those compounds of Formula Ia: ##STR17## wherein: Z is selected from a bond (i.e. is absent), O, or S; and/or
R2 is selected from H, aryl(C1 -C10 alkoxy)carbonyl, or C1 -C10 alkoxycarbonyl; and/or
W is --(CH2)n C(═O)N(R5a)--; and/or
X is --(C(R4)2)n --C(R4)(R8)--CH(R4)--, with the proviso that when n is 0 or 1, then at least one of R4a or R8 is other than H or methyl; and/or
R5 is selected from H or C1 -C10 alkyl substituted with 0-6 R4b ; and/or
R6 is selected from H, C1 -C10 alkyl, hydroxy, C1 -C10 alkoxy, nitro, C1 -C10 alkylcarbonyl, --N(R12)R13, --NR5 R5a, CO2 R5, S(O)m R5, OR5, cyano, halo;
C6 to C10 aryl optionally substituted with 1-3 groups selected from halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m Me, or --NMe2 ;
C7 to C11 arylalkyl, said aryl being optionally substituted with 1-3 groups selected from halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m Me, or --NMe2 ;
methylenedioxy when R6 is a substituent on aryl; or
a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R7 ; and/or
R7 is selected from selected from H, C1 -C10 alkyl, hydroxy, C1 -C10 alkoxy, nitro, C1 -C10 alkylcarbonyl, --N(R12)R13, cyano, or halo; and/or
R8 is selected from:
--CONR5 NR5a ; --CO2 R5 ;
C1 -C10 alkyl, substituted with 0-3 R6 ;
C2 -C10 alkenyl, substituted with 0-3 R6 ;
C2 -C10 alkynyl, substituted with 0-3 R6,
C3 -C8 cycloalkyl, substituted with 0-3 R6 ;
C5 -C6 cycloalkenyl, substituted with 0-3 R6 ;
aryl, substituted with 0-2 R6 ;
5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R6 ; and/or
R12 and R13 are each independently selected from H, C1 -C10 alkyl, C1 -C10 alkoxycarbonyl, C1 -C10 alkylcarbonyl, C1 -C10 alkylsulfonyl, aryl(C1 -C10 alkyl)sulfonyl, arylsulfonyl, aryl, heteroarylcarbonyl, or heteroarylalkylcarbonyl, wherein said aryls are optionally substituted with 0-3 substituents selected from the group consisting of: C1 -C4 alkyl, C1 -C4 alkoxy, halo, CF3, and NO2.
[8] Further preferred compounds of this second embodiment are those compounds of Formula Ia: ##STR18## wherein: Z is selected from a bond (i.e. is absent) or O; and/or
W is --(CH2)n C(═O)N(R12)--; and/or
X is --C(R4)(R8)--C(R4)2 --.
[9] Further preferred compounds of this second embodiment are compounds of Formula Ia, wherein:
R1 is R2 NHC(═NR2)--, R2 NHC(═NR2)NH-- and V is phenylene or pyridylene, or
R1 is ##STR19## and V is a single bond (i.e. V is absent); n is 1 or 2;
X is --CHR8 CH2 --;
Y is selected from:
hydroxy;
C1 to C10 alkoxy;
methylcarbonyloxymethoxy-;
ethylcarbonyloxymethoxy-;
t-butylcarbonyloxymethoxy-;
cyclohexylcarbonyloxymethoxy-;
1-(methylcarbonyloxy)ethoxy-;
1-(ethylcarbonyloxy)ethoxy-;
1-(t-butylcarbonyloxy)ethoxy-;
1-(cyclohexylcarbonyloxy)ethoxy-;
i-propyloxycarbonyloxymethoxy-;
t-butyloxycarbonyloxymethoxy-;
1-(i-propyloxycarbonyloxy)ethoxy-;
1-(cyclohexyloxycarbonyloxy)ethoxy-;
1-(t-butyloxycarbonyloxy)ethoxy-;
dimethylaminoethoxy-;
diethylaminoethoxy-;
(5-methyl-1,3-dioxacyclopenten-2-on-4-yl)methoxy-;
(5-(t-butyl)-1,3-dioxacyclopenten-2-on-4-yl)methoxy-;
(1,3-dioxa-5-phenyl-cyclopenten-2-on-4-yl)methoxy-;
1-(2-(2-methoxypropyl)carbonyloxy)ethoxy-;
R6 is selected from H, C1 -C4 alkyl, hydroxy, C1 -C4 alkoxy, nitro, C1 -C10 alkylcarbonyl, --N(R12)R13, --NR5 R5a, CO2 R5, S(O)m R5, OR5, cyano, halo;
C6 to C10 aryl optionally substituted with 1-3 groups selected from halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m Me, or --NMe2 ;
methylenedioxy when R6 is a substituent on aryl; or
a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyridinyl, 3H-indolyl, carbazolyl, pyrrolidinyl, piperidinyl, indolinyl, isoxazolinyl or morpholinyl;
R8 is selected from:
--CONR5 NR5a ; --CO2 R5 ;
C1 -C10 alkyl, substituted with 0-3 R6 ;
C2 -C10 alkenyl, substituted with 0-3 R6 ;
C2 -C10 alkynyl, substituted with 0-3 R6,
C3 -C8 cycloalkyl, substituted with 0-3 R6 ; aryl, substituted with 0-2 R6 ;
a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, isoxazolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyridinyl, 3H-indolyl, carbazolyl, pyrrolidinyl, piperidinyl, indolinyl, or morpholinyl, said heterocyclic ring being substituted with 0-2 R6 ;
R12 is selected from H, C1 -C6 alkyl, C1 -C4 alkoxycarbonyl, C1 -C6 alkylcarbonyl, C1 -C6 alkylsulfonyl, aryl(C1 -C4 alkyl)sulfonyl, arylsulfonyl, aryl, pyridylcarbonyl or pyridylmethylcarbonyl, wherein said aryls are optionally substituted with 0-3 substituents selected from the group consisting of: C1 -C4 alkyl, C1 -C4 alkoxy, halo, CF3, and NO2 ; and
R13 is H.
[10], [35] Specifically preferred compounds of this second embodiment are compounds, or enantiomeric or diasteriomeric forms thereof, or mixtures of enantiomeric or diasteriomeric forms thereof, or a pharmaceutically acceptable salt or prodrug forms thereof, selected from:
3(R,S)-{5(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-ylacetyl]amino}-3-phenylpropanoic acid;
3(R,S)-{5(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-ylacetyl]amino}-pentanoic acid;
3(R)-{5(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-ylacetyl]amino}heptanoic acid;
3(R,S)-{5(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-ylacetyl]amino}-4-(phenylthio)butanoic acid;
3(R,S)-{5(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-ylacetyl]amino}-4-(phenylsulfonamido)butanoic acid;
3(R,S)-{5(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-ylacetyl]amino}-4-(n-butylsulfonamido)butanoic acid;
3(S)-{5(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-ylacetyl]amino}-3-(adamantylmethylaminocarbonyl)propanoic acid;
3(S)-{5(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-ylacetyl]amino}-3-(1-azabicyclo[3.2.2]nonylcarbonyl)propanoic acid;
3(S)-{5(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-ylacetyl]amino}-3-(phenethylaminocarbonyl)propanoic acid;
3(R)-{5(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-ylacetyl]amino}-3-(3-pyridylethyl)propanoic acid;
3(R)-{5(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-ylacetyl]amino}-3-(2-pyridylethyl)propanoic acid;
3(R)-{5(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-ylacetyl]amino}-3-(phenylpropyl)propanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(phenylsulfonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(4-methyl-phenyl-sulfonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(butanesulfonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(propanesulfonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(ethanesulfonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(methyloxycarbonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(ethyloxycarbonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(1-propyloxycarbonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(2-propyloxycarbonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(n-butyloxycarbonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(1-(2-methyl)-propyloxycarbonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(2-(2-methyl)-propyloxycarbonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(benzyloxycarbonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(4-methylbenzyloxycarbonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(4-methoxybenzyloxycarbonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(4-chlorobenzyloxycarbonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(4-bromobenzyloxycarbonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(4-fluorobenzyloxycarbonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(4-phenoxybenzyloxycarbonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(2-(methyloxyethyl)-oxycarbonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(2-pyridinylcarbonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(3-pyridinylcarbonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(4-pyridinyl-carbonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(2-(2-pyridinyl)-acetyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(2-(3-pyridinyl)-acetyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(2-(4-pyridinyl)-acetyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(2-pyridyl-methyloxycarbonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(3-pyridyl-methyloxycarbonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(4-pyridyl-methyloxycarbonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(4-butyloxyphenylsulfonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(2-thienylsulfonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(3-methylphenylsulfonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(4-iodophenylsulfonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(3-trifluoromethylphenylsulfonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(3-chlorophenylsulfonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(3-2-methoxycarbonylphenylsulfonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(2,4,6-trimethylphenylsulfonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(2-chlorophenylsulfonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(4-trifluoromethylphenylsulfonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(2-trifluoromethylphenylsulfonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(2-fluorophenylsulfonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(4-fluorophenylsulfonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(4-methoxyphenylsulfonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(2,3,5,6-tetramethylphenylsulfonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2-(4-cyanophenylsulfonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(4-chlorophenylsulfonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(4-propylphenylsulfonyl)-2,3-diaiminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(2-phenylethylsulfonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(4-isopropylphenylsulfonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(3-phenylpropylsulfonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(3-pyridylsulfonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(phenylaminosulfonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(benzylaminosulfonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(dimethylaminosulfonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(2-fluoro-4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(3-methylphenylsulfonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(2-formamidino-5-pyridinyl)-isoxazolin-5-yl}-acetyl]-N2 -(n-butyloxycarbonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(2-formamidino-5-pyridinyl)-isoxazolin-5-yl}-acetyl]-N2 -(3-methylphenylsulfonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(3-formamidino-6-pyridinyl)-isoxazolin-5-yl}-acetyl]-N2 -(n-butyloxycarbonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(3-formamidino-6-pyridinyl)-isoxazolin-5-yl}-acetyl]-N2 -(3-methylphenylsulfonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(phenylaminocarbonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(4-fluorophenylaminocarbonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(1-naphthylaminocarbonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(benzylaminocarbonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(3-bromo-2-thienylsulfonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(3-methyl-2-benzothienylsulfonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(isobutyloxycarbonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(isobutyloxycarbonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(isobutyloxycarbonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(2-cyclopropylethoxycarbonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(4-guanidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(n-butyloxycarbonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(4-guanidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(3-methylphenylsulfonyl)-2,3-diaminopropanoic acid;
N3 -[2-{5-(4-formamidinophenyl)-isoxazolin-3-yl}-acetyl]-N2 -(n-butyloxycarbonyl)-2,3-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(2-bromo-phenylsulfonyl)-2,3-diaminopropionic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(2-methyl-phenylsulfonyl)-2,3-diaminopropionic acid;
N3 -[2-{3-(3-formamidino-6-pyridinyl)-isoxazolin-5-yl}-acetyl]-N2 -(3-methylphenylsulfonyl)-2,3-diaminopropionic acid;
N3 -[2-{3-(2-formamidino-5-pyridinyl)-isoxazolin-5-yl}-acetyl]-N2 -(3-methylphenylsulfonyl)-2,3-diaminopropionic acid;
N3 -[2-{3-(2-fluoro-4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(3-methylphenylsulfonyl)-2,3-diaminopropionic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(3-bromo-phenylsulfonyl)-2,3-diaminopropionic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5-yl}-acetyl]-N2 -(4-bromo-phenylsulfonyl)-2,3-diaminopropionic acid;
said enantiomeric and diasteriomeric forms being selected from:
(R,S), (R,S);
(R), (R,S);
(S), (R, S);
(R), (R);
(S), (R);
(R), (S);
(S), (S).
The prodrug forms of the compounds of the second embodiment include the following esters:
methyl;
ethyl;
isopropyl;
methylcarbonyloxymethyl-;
ethylcarbonyloxymethyl-;
t-butylcarbonyloxymethyl-;
cyclohexylcarbonyloxymethyl-;
1-(methylcarbonyloxy)ethyl-;
1-(ethylcarbonyloxy)ethyl-;
1-(t-butylcarbonyloxy)ethyl-;
1-(cyclohexylcarbonyloxy)ethyl-;
i-propyloxycarbonyloxymethyl-;
cyclohexylcarbonyloxymethyl-;
t-butyloxycarbonyloxymethyl-;
1-(i-propyloxycarbonyloxy)ethyl-;
1-(cyclohexyloxycarbonyloxy)ethyl-;
1-(t-butyloxycarbonyloxy)ethyl-;
dimethylaminoethyl-;
diethylaminoethyl-;
(5-methyl-1,3-dioxacyclopenten-2-on-4-yl)methyl-;
(5-(t-butyl)-1,3-dioxacyclopenten-2-on-4-yl)methyl-;
(1,3-dioxa-5-phenyl-cyclopenten-2-on-4-yl)methyl-;
1-(2-(2-methoxypropyl)carbonyloxy)ethyl-.
[11] Also preferred compounds of the second embodiment are those compounds of Formula Ic: ##STR20## wherein: b is a single or double bond;
R1 is selected from R2a (R3)N--, R2 (R3)N(R2 N═)C--, R2a (R3)N(CH2)q Z--, R2 (R3)N(R2 N═)C(CH2)q Z--, R2 (R3)N(R2 N═)CN(R2)--, R2 (R3)NC(O)--, R2 (R5 O)N(R2 N═)C--, or R2 (R3)N(R5 ON═)C--; ##STR21## Z is selected from a bond (i.e. is absent), O, or S; R2 and R3 are independently selected from: H; C1 -C6 alkyl; C7 -C11 arylalkyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m CH3, --N(CH3)2, C1 -C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C1 -C10 alkoxycarbonyl; aryl(C1 -C10 alkoxy)carbonyl where the aryl group is optionally substituted with 0-3 groups selected from hydroxy, halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m CH3, --N(CH3)2, C1 -C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; or heteroaryl(C1 -C5)alkyl where the heteroaryl group is optionally substituted with 0-2 groups selected from hydroxy, halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m CH3, --N(CH3)2, C1 -C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl;
R2a is R2 or R2 (R3)N(R2 N═)C;
U is a single bond (i.e., U is not present),
V is selected from:
a single bond (i.e., V is not present);
--(C1 -C7 alkyl)-, substituted with 0-3 groups independently selected from R6 or R7 ;
--(C2 -C7 alkenyl)-, substituted with 0-3 groups independently selected from R6 or R7 ;
--(C2 -C7 alkynyl)-, substituted with 0-3 groups independently selected from R6 or R7 ;
--(phenyl)-Q-, said phenyl substituted with 0-2 groups independently selected from R6 or R7 ;
--(pyridyl)-Q-, said pyridyl substituted with 0-2 groups independently selected from R6 or R7 ; or
-(pyridazinyl)-Q-, said pyridazinyl substituted with 0-2 groups independently selected from R6 or R7,
Q is selected from
a single bond (i.e., Q is not present), --O--, --S(O)m --, --N(R12)--, --(CH2)m --, --C(═O)--, --N(R5a)C(═O)--, --C(═O)N(R5a)--, --CH2 O--, --OCH2 --, --CH2 N(R12)--, --N(R12)CH2 --, --CH2 C(═O)--, --C(═O)CH2 --, --CH2 S(O)m --, or --S(O)m CH2 --,
provided that when b is a single bond, and R1 --U--V-- is a substituent on C5 of the central 5-membered ring in Formula I, then Q is not --O--, --S(O)m --, --N(R12)--, --C(═O)N(R5a)--, --CH2 O--, CH2 N(R12)-- or --CH2 S(O)m --;
W is selected from:
--(C(R4)2)--C(═O)--N(R5a)--, or --C(═O)--N(R5a)--(C(R4)2)--;
X is --C(R4)2 --CHR4a --;
R4 is selected from H, C1 -C10 alkyl, C1 -C10 alkylcarbonyl, aryl, arylalkyl, cycloalkyl, or cycloalkylalkyl;
R4a is selected from hydroxy, C1 -C10 alkoxy, nitro, --N(R5)R5a, --N(R12)R13, or --N(R16)R17, C1 -C10 alkyl substituted with 0-3 R6, aryl substituted with 0-3 R6, heteroaryl substituted with 0-3 R6, or C1 -C10 alkylcarbonyl;
R4b is selected from H, C1 -C6 alkyl, C2 -C6 alkenyl, C2 -C6 alkynyl, hydroxy, C1 -C6 alkoxy, C1 -C6 alkylthio, C1 -C6 alkylsulfinyl, C1 -C6 alkylsulfonyl, nitro, C1 -C6 alkylcarbonyl, C6 -C10 aryl, --N(R12)R13, halo, CF3, CN, C1 -C6 alkoxycarbonyl, carboxy, piperidinyl, morpholinyl or pyridyl;
R5 is selected from H or C1 -C10 alkyl substituted with 0-6 R4b ;
R5a is selected from hydrogen, hydroxy, C1 to C8 alkyl, C2 to C6 alkenyl, C3 to C11 cycloalkyl, C4 to C11 cycloalkylmethyl, C1 -C6 alkoxy, benzyloxy, C6 to C10 aryl, heteroaryl, heteroarylalkyl, C7 to C11 arylalkyl, or adamantylmethyl, C1 -C10 alkyl substituted with 0-2 R4b ;
alternately, R5 and R5a can be taken together to be 3-azabicyclononyl, 1,2,3,4-tetrahydro-1-quinolinyl, 1,2,3,4-tetrahydro-2-isoquinolinyl, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl or 1-piperazinyl, each being optionally substituted with C1 -C6 alkyl, C6 -C10 aryl, heteroaryl, C7 -C11 arylalkyl, C1 -C6 alkylcarbonyl, C3 -C7 cycloalkylcarbonyl, C1 -C6 alkoxycarbonyl or C7 -C11 arylalkoxycarbonyl;
R5b is selected from C1 -C8 alkyl, C2 -C6 alkenyl, C3 -C11 cycloalkyl, C4 -C11 cycloalkylmethyl, C6 -C10 aryl, C7 -C11 arylalkyl, or C1 -C10 alkyl substituted with 0-2 R4b
Y is selected from hydroxy, C1 to C10 alkyloxy, C3 to C11 cycloalkyloxy, C6 to C10 aryloxy, C7 to C11 aralkyloxy, C3 to C10 alkylcarbonyloxyalkyloxy, C3 to C10 alkoxycarbonyloxyalkyloxy, C2 to C10 alkoxycarbonylalkyloxy, C5 to C10 cycloalkylcarbonyloxyalkyloxy, C5 to C10 cycloalkoxycarbonyloxyalkyloxy, C5 to C10 cycloalkoxycarbonylalkyloxy, C7 to C11 aryloxycarbonylalkyloxy, C8 to C12 aryloxycarbonyloxyalkyloxy, C8 to C12 arylcarbonyloxyalkyloxy, C5 to C10 alkoxyalkylcarbonyloxyalkyloxy, C5 to C10 (5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, or C10 to C14 (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy;
R6 and R7 are each independently selected from H, C1 -C10 alkyl, hydroxy, C1 -C10 alkoxy, nitro, C1 -C10 alkylcarbonyl, --N(R12)R13, cyano, or halo;
R12 and R13 are each independently selected from H, C1 -C10 alkyl, C1 -C10 alkoxycarbonyl, C1 -C10 alkylcarbonyl, C1 -C10 alkylsulfonyl, aryl(C1 -C10 alkyl)sulfonyl, arylsulfonyl, heteroarylcarbonyl, heteroarylalkylcarbonyl or aryl, wherein said aryls are optionally substituted with 0-3 substituents selected from the group consisting of: C1 -C4 alkyl, C1 -C4 alkoxy, halo, CF3, and NO2 ;
R15 is selected from H, C1 -C10 alkyl, C2 -C10 alkenyl, C2 -C10 alkynyl, C1 -C10 alkoxy, aryl, heteroaryl or C1 -C10 alkoxycarbonyl, CO2 R5 or --C(═O)N(R5)R5a ;
R16 is selected from:
--C(═O)--O--R18a,
--C(═O)--R18b,
--C(═O)N(R18b)2,
--SO2 --R18a, or
--SO2 --N(R18b)2 ;
R17 is selected from: H or C1 -C4 alkyl;
R18a is selected from:
C1 -C8 alkyl substituted with 0-2 R19,
C2 -C8 alkenyl substituted with 0-2 R19,
C2 -C8 alkynyl substituted with 0-2 R19,
C3 -C8 cycloalkyl substituted with 0-2 R19,
aryl substituted with 0-4 R19,
aryl(C1 -C6 alkyl)-substituted with 0-4 R19,
a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, isoxazolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyrimidinyl, 3H-indolyl, carbazolyl, pyrrolidinyl, piperidinyl, indolinyl, or morpholinyl, said heterocyclic ring being substituted with 0-4 R19 ;
C1 -C6 alkyl substituted with a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolinyl, benzofuranyl, indolyl, indolenyl, quinolinyl, isoquinolinyl,.benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyridinyl, 3H-indolyl, indolyl, carbazole, pyrrolidinyl, piperidinyl, indolinyl, or morpholinyl, said heterocyclic ring being substituted with 0-4 R19 ;
R18b is selected from R18a or H;
R19 is selected from H, halogen, CF3, CN, NO2, NR12 R13, C1 -C8 alkyl; C2 -C6 alkenyl, C2 -C6 alkynyl, C1 -C6 alkoxy, C3 -C11 cycloalkyl, C4 -C11 cycloalkylalkyl, aryl, heteroaryl, aryl(C1 -C6 alkyl)-, or C1 -C4 alkoxycarbonyl;
n is 0-4;
q is 1-7;
r is 0-3;
provided that n, q, and r are chosen such that the number of atoms between R1 and Y is in the range of 8-17.
[12] Further preferred compounds of the second embodiment of Formula Ic are those compounds of Formula Ib: ##STR22## wherein: R1 is selected from: R2 (R3)N--, R2 NH(R2 N═)C--, R2 NH(R2 N═)CNH--, R2 R3 N(CH2)p' Z--, R2 NH(R2 N═)CNH(CH2)p" Z--, R2 (R3)NC(O)--, R2 (R5 O)N(R2 N═)C--, or R2 (R3)N(R5 ON═)C--; ##STR23## n is 0-1; p' is 4-6;
p" is 2-4;
Z is selected from a bond (i.e. is absent) or O;
V is a single bond (i.e., V is not present), -(phenyl)- or -(pyridyl)-;
W is selected from:
--(C(R4)2)--C(═O)--N(R5a)--,
--C(═O)--N(R5a)--CH2 --;
X is selected from:
--CH2 --CHN(R16)R17 --, or
--CH2 --CHNR5 R5a --;
Y is selected from:
hydroxy;
C1 to C10 alkoxy;
methylcarbonyloxymethoxy-;
ethylcarbonyloxymethoxy-;
t-butylcarbonyloxymethoxy-;
cyclohexylcarbonyloxymethoxy-;
1-(methylcarbonyloxy)ethoxy-;
1-(ethylcarbonyloxy)ethoxy-;
1-(t-butylcarbonyloxy)ethoxy-;
1-(cyclohexylcarbonyloxy)ethoxy-;
i-propyloxycarbonyloxymethoxy-;
t-butyloxycarbonyloxymethoxy-;
1-(i-propyloxycarbonyloxy)ethoxy-;
1-(cyclohexyloxycarbonyloxy)ethoxy-;
1-(t-butyloxycarbonyloxy)ethoxy-;
dimethylaminoethoxy-;
diethylaminoethoxy-;
(5-methyl-1,3-dioxacyclopenten-2-on-4-yl)methoxy-;
(5-(t-butyl)-1,3-dioxacyclopenten-2-on-4-yl)methoxy-;
(1,3-dioxa-5-phenyl-cyclopenten-2-on-4-yl)methoxy-;
1-(2-(2-methoxypropyl)carbonyloxy)ethoxy-;
R16 is selected from:
--C(═O)--O--R18a,
--C(═O)--R18b,
--S(═O)2 --R18a or
--SO2 --N(R18b)2 ;
R17 is selected from H or C1 -C5 alkyl;
R18a is selected from:
C1 -C8 alkyl substituted with 0-2 R19,
C2 -C8 alkenyl substituted with 0-2 R19,
C2 -C8 alkynyl substituted with 0-2 R19,
C3 -C8 cycloalkyl substituted with 0-2 R19,
aryl substituted with 0-4 R19,
aryl(C1 -C6 alkyl)-substituted with 0-4 R19,
a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, isoxazolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyrimidinyl, 3H-indolyl, carbazolyl, pyrrolidinyl, piperidinyl, indolinyl, or morpholinyl, said heterocyclic ring being substituted with 0-4 R19 ;
C1 -C6 alkyl substituted with a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolinyl, benzofuranyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyridinyl, 3H-indolyl, indolyl, carbazole, pyrrolidinyl, piperidinyl, indolinyl, or morpholinyl, said heterocyclic ring being substituted with 0-4 R19.
[13] Further preferred compounds of Formula Ib are those compounds wherein:
R1 is R2 NH(R2 N═)C-- or R2 HN(R2 N═)CNH-- and V is phenylene or pyridylene; or
R1 is ##STR24## and V is a single bond (i.e. V is absent); n is 1 or 2;
R18a is selected from:
C1 -C4 alkyl substituted with 0-2 R19,
C2 -C4 alkenyl substituted with 0-2 R19,
C2 -C4 alkynyl substituted with 0-2 R19,
C3 -C7 cycloalkyl substituted with 0-2 R19,
aryl substituted with 0-4 R19,
aryl(C1 -C4 alkyl)-substituted with 0-4 R19,
a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, isoxazolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyrimidinyl, 3H-indolyl, carbazolyl, pyrrolidinyl, piperidinyl, indolinyl, isoxazolinyl or morpholinyl, said heterocyclic ring being substituted with 0-4 R19 ;
C1 -C4 alkyl substituted with a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolinyl, benzofuranyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyridinyl, 3H-indolyl, indolyl, carbazole, pyrrolidinyl, piperidinyl, indolinyl, isoxazolinyl or morpholinyl, said heterocyclic ring being substituted with 0-4 R19.
[14] Specifically preferred compounds of Formula Ib are compounds, or pharmaceutically acceptable salt forms thereof, selected from:
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(phenylsulfonyl)-2,3-(S)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(4-methyl-phenyl-sulfonyl)-2,3-(S)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(butanesulfonyl)-2,3-(S)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(propanesulfonyl)-2,3-(S)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(ethanesulfonyl)-2,3-(S)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(methyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(ethyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(1-propyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(2-propyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(n-butyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R)-yl}-acetyl]-N2-(n-butyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(S)-yl}-acetyl]-N2-(n-butyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R)-yl}-acetyl]-N2-(n-butyloxycarbonyl)-2,3-(R)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(S)-yl}-acetyl]-N2-(n-butyloxycarbonyl)-2,3-(R)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(2-butyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(1-(2-methyl)-propyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(2-(2-methyl)-propyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(benzyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R)-yl}-acetyl]-N2-(benzyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(S)-yl}-acetyl]-N2-(benzyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(4-methylbenzyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(4-methoxybenzyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(4-chlorobenzyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(4-bromobenzyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(4-fluorobenzyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(4-phenoxybenzyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(2-(methyloxyethyl)-oxycarbonyl)-2,3-(S)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(2-pyridinylcarbonyl)-2,3-(S)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(3-pyridinylcarbonyl)-2,3-(S)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(4-pyridinyl-carbonyl)-2,3-(S)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(2-(2-pyridinyl)-acetyl)-2,3-(S)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(2-(3-pyridinyl)-acetyl)-2,3-(S)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(2-(4-pyridinyl)-acetyl)-2,3-(S)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(2-pyridyl-methyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(3-pyridyl-methyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(4-pyridyl-methyloxycarbonyl)-2,3-(S)-diaminopropanoic acid.
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(4-butyloxyphenylsulfonyl)-2,3-(S)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(2-thienylsulfonyl)-2,3-(S)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(3-methylphenylsulfonyl)-2,3-(R,S)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(3-methylphenylsulfonyl)-2,3-(S)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(3-methylphenylsulfonyl)-2,3-(R)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R)-yl}-acetyl]-N2-(3-methylphenylsulfonyl)-2,3-(S)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(S)-yl}-acetyl]-N2-(3-methylphenylsulfonyl)-2,3-(S)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(S)-yl}-acetyl]-N2-(3-methylphenylsulfonyl)-2,3-(R)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R)-yl}-acetyl]-N2-(3-methylphenylsulfonyl)-2,3-(R)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(4-iodophenylsulfonyl)-2,3-(S)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(3-trifluoromethylphenylsulfonyl)-2,3-(S)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(3-chlorophenylsulfonyl)-2,3-(S)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(3-2-methoxycarbonylphenylsulfonyl)-2,3-(S)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(2,4,6-trimethylphenylsulfonyl)-2,3-(S)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(2-chlorophenylsulfonyl)-2,3-(S)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(4-trifluoromethylphenylsulfonyl)-2,3-(S)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(2-trifluoromethylphenylsulfonyl)-2,3-(S)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(2-fluorophenylsulfonyl)-2,3-(S)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(4-fluorophenylsulfonyl)-2,3-(S)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(4-methoxyphenylsulfonyl)-2,3-(S)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(2,3,5,6-tetramethylphenylsulfonyl)-2,3-(S)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(4-cyanophenylsulfonyl)-2,3-(S)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(4-chlorophenylsulfonyl)-2,3-(S)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(4-propylphenylsulfonyl)-2,3-(S)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(2-phenylethylsulfonyl)-2,3-(S)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(4-isopropylphenylsulfonyl)-2,3-(S)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(3-phenylpropylsulfonyl)-2,3-(S)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(3-pyridylsulfonyl)-2,3-(S)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(phenylaminosulfonyl)-2,3-(S)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(benzylaminosulfonyl)-2,3-(S)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(dimethylaminosulfonyl)-2,3-(S)-diaminopropanoic acid,
N3 -[2-{3-(2-fluoro-4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(3-methylphenylsulfonyl)-2,3-(S)-diaminopropanoic acid,
N3 -[2-{3-(2-formamidino-5-pyridinyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(n-butyloxycarbonyl)-2,3-(S)-diaminopropanoic acid,
N3 -[2-{3-(2-formamidino-5-pyridinyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(3-methylphenylsulfonyl)-2,3-(S)-diaminopropanoic acid,
N3 -[2-{3-(3-formamidino-6-pyridinyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(n-butyloxycarbonyl)-2,3-(S)-diaminopropanoic acid,
N3 -[2-{3-(3-formamidino-6-pyridinyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(3-methylphenylsulfonyl)-2,3-(S)-diaminopropanoic acid,
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(phenylaminocarbonyl)-2,3-(S)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(4-fluorophenylaminocarbonyl)-2,3-(S)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(1-naphthylaminocarbonyl)-2,3-(S)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(benzylaminocarbonyl)-2,3-(S)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(3-bromo-2-thienylsulfonyl)-2,3-(S)-diaminopropanoic acid;
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(3-methyl-2-benzothienylsulfonyl)-2,3-(S)-diaminopropanoic acid,
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(isobutyloxycarbonyl)-2,3-(S)-diaminopropanoic acid,
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R)-yl}-acetyl]-N2-(isobutyloxycarbonyl)-2,3-(S)-diaminopropanoic acid,
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(S)-yl}-acetyl]-N2-(isobutyloxycarbonyl)-2,3-(S)-diaminopropanoic acid,
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(2-cyclopropylethoxycarbonyl)-2,3-(S)-diaminopropanoic acid,
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(R)-yl}-acetyl]-N2-(2-cyclopropylethoxycarbonyl)-2,3-(S)-diaminopropanoic acid, and
N3 -[2-{3-(4-formamidinophenyl)-isoxazolin-5(S)-yl}-acetyl]-N2-(2-cyclopropylethoxycarbonyl)-2,3-(S)-diaminopropanoic acid.
N3 -[2-{3-(4-guanidinophenyl)-isoxazolin-5(R,S)-yl}-acetyl]-N2-(n-butyloxycarbonyl)-2,3-(S)-diaminopropanoic acid.
N3 -[2-{3-(4-guanidinophenyl)-isoxazolin-5(R)-yl}-acetyl]-N2-(n-butyloxycarbonyl)-2,3-(S)-diaminopropanoic acid.
N3 -[2-{3-(4-guanidinophenyl)-isoxazolin-5(R)-yl}-acetyl]-N2-(3-methylphenylsulfonyl)-2,3-(S)-diaminopropanoic acid.
N3 -[2-{5-(4-formamidinophenyl)-isoxazolin-3(R,S)-yl}-acetyl]-N2-(n-butyloxycarbonyl)-2,3-(S)-diaminopropanoic acid;
[15] Also specifically preferred are prodrug esters of the specifically preferred compounds of Formula Ib, said esters being chosen from the group consisting of:
methyl;
ethyl;
isopropyl;
methylcarbonyloxymethyl-;
ethylcarbonyloxymethyl-;
t-butylcarbonyloxymethyl-;
cyclohexylcarbonyloxymethyl-;
1-(methylcarbonyloxy)ethyl-;
1-(ethylcarbonyloxy)ethyl-;
1-(t-butylcarbonyloxy)ethyl-;
1-(cyclohexylcarbonyloxy)ethyl-;
i-propyloxycarbonyloxymethyl-;
cyclohexylcarbonyloxymethyl-;
t-butyloxycarbonyloxymethyl-;
1-(i-propyloxycarbonyloxy)ethyl-;
1-cyclohexyloxycarbonyloxy)ethyl-;
1-(t-butyloxycarbonyloxy)ethyl-;
dimethylaminoethyl-;
diethylaminoethyl-;
(5-methyl-1,3-dioxacyclopenten-2-on-4-yl)methyl-;
(5-(t-butyl)-1,3-dioxacyclopenten-2-on-4-yl)methyl-;
(1,3-dioxa-5-phenyl-cyclopenten-2-on-4-yl)methyl-;
1-(2-(2-methoxypropyl)carbonyloxy)ethyl-.
[16] A third embodiment of this invention provides a compound of Formula Id: ##STR25## or a pharmaceutically acceptable salt or prodrug form thereof wherein: R1 is selected from is selected from R2 (R3)N--, R2 (R3)N(R2 N═)C--, R2 (R3)N(R2 N═)CN(R2)--, R2 (R3)N(CH2)q Z--, R2 (R3)N(R2 N═)C(CH2)q Z--, R2 (R3)N(R2 N═)CN(R2)(CH2)q Z--, piperazinyl-(CH2)q Z--, R2 (R3)NC(O)--, R2 (R5 O)N(R2 N═)C--, R2 (R3)N(R5 ON═)C--, ##STR26## Z is selected from a bond (i.e., is absent), O, S, S(═O), or S(═O)2 ;
R2 and R3 are independently selected from: H; C1 -C10 alkyl; C3 -C6 alkenyl; C3 -C11 cycloalkyl; C4 -C11 cycloalkylalkyl; C6 -C10 aryl optionally substituted with 0-3 groups selected from hydroxy, halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m CH3, --N(CH3)2, C1 -C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; , C7 -C11 arylalkyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m CH3, --N(CH3)2, C1 -C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C2 -C7 alkylcarbonyl; C7 -C11 arylcarbonyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m CH3, --N(CH3)2, C1 -C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C1 -C10 alkoxycarbonyl; C4 -C11 cycloalkoxycarbonyl; C7 -C11 bicycloalkoxycarbonyl; C7 -C11 aryloxycarbonyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m CH3, --N(CH3)2, C1 -C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; aryl(C1 -C10 alkoxy)carbonyl where the aryl group is optionally substituted with 0-3 groups selected from hydroxy, halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m CH3, --N(CH3)2, C1 -C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C1 -C6 alkylcarbonyloxy(C1 -C4 alkoxy)carbonyl; C6 -C10 arylcarbonyloxy(C1 -C4 alkoxy)carbonyl where the aryl group is optionally substituted with 0-3 groups selected from hydroxy, halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m CH3, --N(CH3)2, C1 -C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C4 -C11 cycloalkylcarbonyloxy(C1 -C4 alkoxy)carbonyl; heteroaryl optionally substituted with 0-2 groups selected from hydroxy, halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m CH3, --N(CH3)2, C1 -C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; or heteroaryl(C1 -C5)alkyl where the heteroaryl group is optionally substituted with 0-2 groups selected from hydroxy, halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m CH3, --N(CH3)2, C1 -C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl;
provided that only one of R2 and R3 may be hydroxy;
U is selected from:
a single bond (i.e., U is absent)
C1 -C7 alkylene,
C2 -C7 alkenylene,
C2 -C7 alkynylene,
arylene substituted with 0-3 R6a,, or
pyridylene substituted with 0-3 R6a ;
V is selected from:
a single bond (i.e., V is absent);
C1 -C7 alkylene substituted with 0-6 R6 or R7 ;
C2 -C7 alkenylene substituted with 0-4 R6 or R7 ;
C2 -C7 alkynylene substituted with 0-4 R6 or R7 ;
phenylene substituted with 0-4 R6 or R7 ;
pyridylene substituted with 0-3 R6 or R7 ;
pyridazinylene substituted with 0-3 R6 or R7 ;
X is selected from:
a single bond (i.e., X is absent);
--(CH2)n C(═O)N(R12)--;
C1 -C7 alkylene substituted with 0-6 R4, R8 or R15 ;
C2 -C7 alkenylene substituted with 0-4 R4, R8 or R15 ;
C2 -C7 alkynylene substituted with 0-4 R4, R8 or R15 ;
Y is selected from:
hydroxy,
C1 to C10 alkyloxy,
C3 to C11 cycloalkyloxy,
C6 to C10 aryloxy,
C7 to C11 aralkyloxy,
C3 to C10 alkylcarbonyloxyalkyloxy,
C3 to C10 alkoxycarbonyloxyalkyloxy,
C2 to C10 alkoxycarbonylalkyloxy,
C5 to C10 cycloalkylcarbonyloxyalkyloxy,
C5 to C10 cycloalkoxycarbonyloxyalkyloxy,
C5 to C10 cycloalkoxycarbonylalkyloxy,
C7 to C11 aryloxycarbonylalkyloxy,
C8 to C12 aryloxycarbonyloxyalkyloxy,
C8 to C12 arylcarbonyloxyalkyloxy,
C5 to C10 alkoxyalkylcarbonyloxyalkyloxy,
C5 to C10 (5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy,
C10 to C14 (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy;
(R2)(R3)N--(C1 -C10 alkoxy)-;
R14 and W are attached to the same carbon and taken together to form a spiro-fused, 5-7 membered ring structure of the formula: ##STR27## D, E, F and G are each independently selected from: C(R6a)2 ;
carbonyl;
a heteroatom moiety selected from N, N(R12), O, provided that no more than 2 of D, E, F and G are N, N(R12), O, S, or C(═O);
alternatively, the bond between D and E, E and F, or F and G in such spiro-fused ring may be a carbon-nitrogen double bond or a carbon--carbon double bond;
R4 is selected from H, C1 -C10 alkyl, hydroxy, C1 -C10 alkoxy, nitro, C1 -C10 alkylcarbonyl, or --N(R12)R13 ;
R6 and R7 are each independently selected from H, C1 -C10 alkyl, hydroxy, C1 -C10 alkoxy, nitro, C1 -C10 alkylcarbonyl, --N(R12)R13, cyano, halo, CF3, CHO, CO2 R5a, C(═O)R5a, CONHR5a, CON(R12)2, OC(═O)R5a, OC(═O)OR5a, OR5a, OC(═O)N(R12)2, OCH2 CO2 R5a, CO2 CH2 CO2 R5a, N(R12)2, NO2, NR12 C(═O)R5a, NR12 C(═O)OR5a, NR12 C(═O)N(R12)2, NR12 SO2 N(R12)2, NR12 SO2 R5a, S(O)p R5a, SO2 N(R12)2, C2 to C6 alkenyl, C3 to C11 cycloalkyl, C4 to C11 cycloalkylmethyl;
C6 to C10 aryl optionally substituted with 1-3 groups selected from halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m Me, or --NMe2 ;
C7 to C11 arylalkyl, said aryl being optionally substituted with 1-3 groups selected from halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m Me, or --NMe2 ;
methylenedioxy when R6 is a substituent on aryl;
R6a is selected from C1 -C4 alkyl, C1 -C4 alkoxy, halo, CF3, NO2, or NR12 R13 ;
R8 is selected from:
H;
R6 ;
C1 -C10 alkyl, substituted with 0-8 R6 ;
C2 -C10 alkenyl, substituted with 0-6 R6 ;
C2 -C10 alkynyl, substituted with 0-6 R6 ;
C3 -C8 cycloalkyl, substituted with 0-6 R6 ;
C5 -C6 cycloalkenyl, substituted with 0-5 R6 ;
aryl, substituted with 0-5 R6 ;
5-6 membered heterocyclic ring containing 1-2 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-5 R6 ;
R12 and R13 are independently H, C1 -C10 alkyl, C1 -C10 alkoxycarbonyl, C1 -C10 alkylcarbonyl, C1 -C10 alkylsulfonyl, aryl(C1 -C10 alkyl)sulfonyl, arylsulfonyl, aryl, C2 -C6 alkenyl, C3 -C11 cycloalkyl, C4 -C11 cycloalkylalkyl, C7 -C11 arylalkyl, C2 -C7 alkylcarbonyl, C7 -C11 arylcarbonyl, C2 -C10 alkoxycarbonyl, C4 -C11 cycloalkoxycarbonyl, C7 -C11 bicycloalkoxycarbonyl, C7 -C11 aryloxycarbonyl, heteroarylcarbonyl, heteroarylalkylcarbonyl or aryl(C1 -C10 alkoxy)carbonyl, wherein said aryls or heteroaryls are optionally substituted with 0-3 substituents selected from the group consisting of: C1 -C4 alkyl, C1 -C4 alkoxy, halo, CF3, and NO2 ;
R5 and R5a are selected independently from H, C1 to C8 alkyl, C2 to C6 alkenyl, C3 to C11 cycloalkyl, C4 to C11 cycloalkylmethyl, C6 to C10 aryl, C7 to C11 arylalkyl, or C1 -C10 alkyl substituted with 0-8 R4 ;
R15 is selected from:
H;
R6 ;
C1 -C10 alkyl, substituted with 0-8 R6 ;
C2 -C10 alkenyl, substituted with 0-6 R6 ;
C1 -C10 alkoxy, substituted with 0-6 R6 ;
aryl, substituted with 0-5 R6 ;
5-6 membered heterocyclic ring containing 1-2 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-5 R6 ;
C1 -C10 alkoxycarbonyl substituted with 0-8 R6 ;
CO2 R5 ; or
--C(═O)N(R12)R13 ;
n is 0-4;
p is 1-3;
q is 1-7;
r is 0-3;
provided that n, p, q and r are chosen such that the number of atoms between R1 and Y is in the range of 8-17.
[47] Also preferred compounds of the second embodiment are those compounds of Formulae Ie or If: ##STR28## or enantiomeric or diasteriomeric forms thereof, or mixtures of enantiomeric or diasteriomeric forms thereof, or a pharmaceutically acceptable salt form thereof, wherein:
R1 is R2 (R3)N(R2 N═)C--, R2 (R3)N(R2 N═)CN(R2)--, or R2 (R3)N--;
R2 and R3 are independently selected from: H; C1 -C10 alkyl; C3 -C6 alkenyl; C3 -C11 cycloalkyl; C4 -C11 cycloalkylalkyl; C6 -C10 aryl optionally substituted with 0-3 groups selected from hydroxy, halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m CH3, --N(CH3)2, C1 -C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C7 -C11 arylalkyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m CH3, --N(CH3)2, C1 -C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C2 -C7 alkylcarbonyl; C7 -C11 arylcarbonyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m CH3, --N(CH3)2, C1 -C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C1 -C10 alkoxycarbonyl; C4 -C11 cycloalkoxycarbonyl; C7 -C11 bicycloalkoxycarbonyl; C7 -C11 aryloxycarbonyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m CH3, --N(CH3)2, C1 -C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; aryl(C1 -C10 alkoxy)carbonyl where the aryl group is optionally substituted with 0-3 groups selected from hydroxy, halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m CH3, --N(CH3)2, C1 -C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C1 -C6 alkylcarbonyloxy(C1 -C4 alkoxy)carbonyl; C6 -C10 arylcarbonyloxy(C1 -C4 alkoxy)carbonyl where the aryl group is optionally substituted with 0-3 groups selected from hydroxy, halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m CH3, --N(CH3)2, C1 -C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C4 -C11 cycloalkylcarbonyloxy(C1 -C4 alkoxy)carbonyl; heteroaryl optionally substituted with 0-2 groups selected from hydroxy, halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m CH3, --N(CH3)2, C1 -C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; or heteroaryl(C1 -C5)alkyl where the heteroaryl group is optionally substituted with 0-2 groups selected from hydroxy, halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m CH3, --N(CH3)2, C1 -C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl;
provided that only one of R2 and R3 may be hydroxy;
R12 and R13 are independently H, C1 -C10 alkyl, C1 -C10 alkoxycarbonyl, C1 -C10 alkylcarbonyl, C1 -C10 alkylsulfonyl, aryl(C1 -C10 alkyl)sulfonyl, arylsulfonyl, aryl(C2 -C10 alkenyl)sulfonyl, heteroarylsulfonyl, aryl, C2 -C6 alkenyl, C3 -C11 cycloalkyl, C4 -C11 cycloalkylalkyl, C7 -C11 arylalkyl, C7 -C11 arylcarbonyl, C4 -C11 cycloalkoxycarbonyl, C7 -C11 bicycloalkoxycarbonyl, C7 -C11 aryloxycarbonyl, heteroarylcarbonyl, heteroarylalkylcarbonyl, or aryl(C1 -C10 alkoxy)carbonyl, wherein said aryls are optionally substituted with 0-3 substituents selected from the group consisting of: C1 -C4 alkyl, C1 -C4 alkoxy, halo, CF3, and NO2 ;
R16 is selected from:
--C(═O)--O--R18a,
--C(═O)--R18b,
--C(═O)N(R18b)2,
--C(═O)NHSO2 R18a,
--C(═O)NHC(═O)R18b,
--C(═O)NHC(═O)OR18a,
--C(═O)NHSO2 NHR18b,
--C(═S)--NH--R18b,
--NH--C(═O)--O--R18a,
--NH--C(═O)--R18b,
--NH--C(═O)--NH--R18b,
--SO2 --O--R18a,
--SO2 --R18a,
--SO2 --N(18b)2,
--SO2 --NHC(═O)O18b,
--P(═S)(OR18a)2,
--P(═O)(OR18a)2,
--P(═S)(R18a)2,
--P(═O)(R18a)2, or ##STR29## R18a is selected from: C1 -C8 alkyl substituted with 0-2 R19,
C2 -C8 alkenyl substituted with 0-2 R19,
C2 -C8 alkynyl substituted with 0-2 R19,
C3 -C8 cycloalkyl substituted with 0-2 R19,
aryl substituted with 0-4 R19,
aryl(C1 -C6 alkyl)-substituted with 0-4 R19,
a 5-10 membered heterocyclic ring system having 1-3 heteroatoms selected independently from O, S, and N, said heterocyclic ring being substituted with 0-4 R19,
C1 -C6 alkyl substituted with a 5-10 membered heterocyclic ring system having 1-3 heteroatoms selected independently from O, S, and N, said heterocyclic ring being substituted with 0-4 R19 ;
R18b is selected from R18a or H;
R19 is selected from H, halogen, CF3, CN, NO2, NR12 R13, C1 -C8 alkyl, C2 -C6 alkenyl, C2 -C6 alkynyl, C3 -C11 cycloalkyl, C4 -C11 cycloalkylalkyl, aryl, aryl(C1 -C6 alkyl)-, C1 -C6 alkoxy, or C1 -C4 alkoxycarbonyl;
Y is selected from hydroxy, C1 to C10 alkyloxy, C3 to C11 cycloalkyloxy, C6 to C10 aryloxy, C7 to C11 aralkyloxy, C3 to C11 alkylcarbonyloxyalkyloxy, C3 to C10 alkoxycarbonyloxyalkyloxy, C2 to C10 alkoxycarbonylalkyloxy, C5 to C10 cycloalkylcarbonyloxyalkyloxy, C5 to C10 cycloalkoxycarbonyloxyalkyloxy, C5 to C10 cycloalkoxycarbonylalkyloxy, C7 to C11 aryloxycarbonylalkyloxy, C8 to C12 aryloxycarbonyloxyalkyloxy, C8 to C12 arylcarbonyloxyalkyloxy, C5 to C10 alkoxyalkylcarbonyloxyalkyloxy, C5 to C10 (5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, C10 to C14 (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, (R2)(R3)N--(C1 -C10 alkoxy)-;
m is 0-2;
n is 0-2; and
p is 1-5.
[17] Preferred compounds of this third embodiment are compounds of Formula III: ##STR30## wherein: R1 is selected from R2 HN--, H2 N(R2 N═)C--, H2 N(R2 N═)CNH--, R2 HN(CH2)q O--, H2 N(R2 N═)CNH(CH2)q O--, piperazinyl-(CH2)q O--, R2 (R3)NC(O)--, R2 (R5 O)N(R2 N═)C--, R2 (R3)N(R5 ON═)C--, ##STR31## R2 and R3 are selected from H; C1 -C6 alkyl; C7 -C11 arylalkyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m CH3, --N(CH3)2, C1 -C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; aryl(C1 -C10 alkoxy)carbonyl where the aryl group is optionally substituted with 0-3 groups selected from hydroxy, halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m CH3, --N(CH3)2, C1 -C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; heteroaryl(C1 -C5)alkyl where the heteroaryl group is optionally substituted with 0-2 groups selected from hydroxy, halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m CH3, --N(CH3)2, C1 -C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; or C1 -C10 alkoxycarbonyl;
R4 is selected from H, C1 -C10 alkyl, hydroxy, C1 -C10 alkoxy, nitro, C1 -C10 alkylcarbonyl, or --N(R12)R13 ;
V is selected from:
a single bond (i.e., V is absent);
C1 -C7 alkylene substituted with 0-6 R6 or R7 ;
C2 -C7 alkenylene substituted with 0-4 R6 or R7 ;
C2 -C7 alkynylene substituted with 0-4 R6 or R7 ;
phenylene substituted with 0-3 R6 or R7 ;
pyridylene substituted with 0-3 R6 or R7 ;
pyridazinylene substituted with 0-3 R6 or R7 ;
X is selected from --(CH2)n C(═O)N(R12)--, C1 -C7 alkylene substituted with 0-1 R4, C2 -C7 alkenylene, or C2 -C7 alkynylene;
Y is selected from:
hydroxy,
C1 to C10 alkyloxy,
C3 to C11 cycloalkyloxy,
C6 to C10 aryloxy,
C7 to C11 aralkyloxy,
C3 to C10 alkylcarbonyloxyalkyloxy,
C3 to C10 alkoxycarbonyloxyalkyloxy,
C2 to C10 alkoxycarbonylalkyloxy,
C5 to C10 cycloalkylcarbonyloxyalkyloxy,
C5 to C10 cycloalkoxycarbonyloxyalkyloxy,
C5 to C10 cycloalkoxycarbonylalkyloxy,
C7 to C11 aryloxycarbonylalkyloxy,
C8 to C12 aryloxycarbonyloxyalkyloxy,
C8 to C12 arylcarbonyloxyalkyloxy,
C5 to C10 alkoxyalkylcarbonyloxyalkyloxy,
C5 to C10 (5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, or
C10 to C14 (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy;
Z is selected from O or CH2 ;
D, E, F and G are each independently selected from:
CH2 ;
carbonyl;
a heteroatom moiety selected from N, NH, O, provided that no more than 2 of D, E, F and G are N, NH, O or S;
alternatively, the bond between D and E, E and F, or F and G in such spiro-fused ring may be a carbon-nitrogen double bond or a carbon--carbon double bond;
R6 and R7 are each independently selected from H, C1 -C10 alkyl, hydroxy, C1 -C10 alkoxy, nitro, C1 -C10 alkylcarbonyl, --N(R12)R13, cyano, or halo;
R12 and R13 are each independently selected from H, C1 -C10 alkyl, C1 -C10 alkoxycarbonyl, C1 -C10 alkylcarbonyl, C1 -C10 alkylsulfonyl, aryl(C1 -C10 alkyl)sulfonyl, arylsulfonyl, heteroarylcarbonyl, heteroaryalkylcarbonyl or aryl;
n is 0-4;
p is 1-3;
q is 1-7;
r is 0-3;
provided that n, p, q and r are chosen such that the number of atoms between R1 and Y is in the range of 8-17.
[18] Further preferred compounds of this third embodiment are compounds of Formula II wherein:
R1 is R2 NHC(═NR2)-- and V is phenyl or pyridyl or
R1 is ##STR32## and V is a single bond (i.e. V is absent); n is 1 or 2;
X is C1 -C4 alkylene substituted with 0-1 R4 ;
Y is selected from:
hydroxy;
C1 to C10 alkoxy;
methylcarbonyloxymethoxy-;
ethylcarbonyloxymethoxy-;
t-butylcarbonyloxymethoxy-;
cyclohexylcarbonyloxymethoxy-;
1-(methylcarbonyloxy)ethoxy-;
1-(ethylcarbonyloxy)ethoxy-;
1-(t-butylcarbonyloxy)ethoxy-;
1-(cyclohexylcarbonyloxy)ethoxy-;
i-propyloxycarbonyloxymethoxy-;
t-butyloxycarbonyloxymethoxy-;
1-(i-propyloxycarbonyloxy)ethoxy-;
1-(cyclohexyloxycarbonyloxy)ethoxy-;
1-(t-butyloxycarbonyloxy)ethoxy-;
dimethylaminoethoxy-;
diethylaminoethoxy-;
(5-methyl-1,3-dioxacyclopenten-2-on-4-yl)methoxy-;
(5-(t-butyl)-1,3-dioxacyclopenten-2-on-4-yl)methoxy-;
(1,3-dioxa-5-phenyl-cyclopenten-2-on-4-yl)methoxy-;
1-(2-(2-methoxypropyl)carbonyloxy)ethoxy-;
R12 and R13 are each independently selected from H, C1 -C6 alkyl, C1 -C4 alkoxycarbonyl, C1 -C4 alkylcarbonyl, C1 -C4 alkylsulfonyl, aryl(C1 -C4 alkyl)sulfonyl, arylsulfonyl, heteroarylcarbonyl, heteroaryalkylcarbonyl or aryl; and
R13 is H.
[19] Specifically preferred compounds of this third embodiment are compounds, or pharmaceutically acceptable salt or prodrug forms thereof, selected from:
5(R,S)-3-(4-amidinophenyl)-8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro[4.4]non-2-ene-7,9-dione;
5(R,S)-3-(4-amidinophenyl)-8-(3-carboxypropyl)-1-oxa-2,8-diazaspiro[4.4]non-2-ene-7,9-dione;
5(R,S)-3-(4-amidinophenyl)-8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro[4.4]non-2-ene-5-one;
5(R,S)-3-(4-amidinophenyl)-8-(3-carboxypropyl)-1-oxa-2,8-diazaspiro[4.4]non-2-ene-5-one;
5(R,S)-3-(4-amidinophenyl)-8-(2-carboxyethyl)-1-oxa-2-azaspiro[4.4]nona-2,8-diene-5-one;
5(R,S)-3-(4-amidinophenyl)-8-(3-carboxypropyl)-1-oxa-2-azaspiro[4.4]nona-2,8-diene-5-one;
5(R,S)-3-(4-amidinophenyl)-8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro[4.4]dec-2-ene-7,9-dione;
5(R,S)-3-(4-amidinophenyl)-8-(3-carboxypropyl)-1-oxa-2,8-diazaspiro[4.4]dec-2-ene-7,9-dione;
5(R,S)-3-(4-amidinophenyl)-8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro[4.4]dec-2-ene-5-one;
5(R,S)-3-(4-amidinophenyl)-8-(3-carboxypropyl)-1-oxa-2,8-diazaspiro[4.4]dec-2-ene-5-one;
5(R,S)-3-(4-amidinophenyl)-8-(2-carboxyethyl)-1-oxa-2-azaspiro[4.4]deca-2,8-diene-5-one;
5(R,S)-3-(4-amidinophenyl)-8-(3-carboxypropyl)-1-oxa-2-azaspiro[4.4]deca-2,8-diene-5-one;
5(R,S)-3-(4-amidinophenyl)-8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro[4.4]undec-2-ene-7,9-dione;
5(R,S)-3-(4-amidinophenyl)-8-(3-carboxypropyl)-1-oxa-2,8-diazaspiro[4.4]undec-2-ene-7,9-dione;
5(R,S)-3-(4-amidinophenyl)-8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro[4.4]undec-2-ene-5-one;
5(R,S)-3-(4-amidinophenyl)-8-(3-carboxypropyl)-1-oxa-2,8-diazaspiro[4.4]undec-2-ene-5-one;
5(R,S)-3-(4-amidinophenyl)-8-(2-carboxyethyl)-1-oxa-2-azaspiro[4.4]undeca-2,8-diene-5-one;
5(R,S)-3-(4-amidinophenyl)-8-(3-carboxypropyl)-1-oxa-2-azaspiro[4.4]undeca-2,8-diene-5-one;
5(R,S)-3-[2-(piperidin-4-yl)ethyl]-8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro[4.4]non-2-ene-7,9-dione;
5(R,S)-3-[2-(piperidin-4-yl)ethyl]-8-(3-carboxypropyl)- 1-oxa-2,8-diazaspiro[4.4]non-2-ene-7,9-dione;
5(R,S)-3-[2-(piperidin-4-yl)ethyl]-8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro[4.4]non-2-ene-5-one;
5(R,S)-3-[2-(piperidin-4-yl)ethyl]-8-(3-carboxypropyl)-1-oxa-2,8-diazaspiro[4.4]non-2-ene-5-one;
5(R,S)-3-[2-(piperidin-4-yl)ethyl]-8-(2-carboxyethyl)-1-oxa-2-azaspiro[4.4]nona-2,8-diene-5-one;
5(R,S)-3-[2-(piperidin-4-yl)ethyl]-8-(3-carboxypropyl)-1-oxa-2-azaspiro[4.4]nona-2,8-diene-5-one;
5(R,S)-3-[2-(piperidin-4-yl)ethyl]-8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro[4.4]dec-2-ene-7,9-dione;
5(R,S)-3-[2-(piperidin-4-yl)ethyl]-8-(3-carboxypropyl)-1-oxa-2,8-diazaspiro[4.4]dec-2-ene-5,7-dione;
5(R,S)-3-[2-(piperidin-4-yl)ethyl]-8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro[4.4]dec-2-ene-5-one;
5(R,S)-3-[2-(piperidin-4-yl)ethyl]-8-(3-carboxypropyl)-1-oxa-2,8-diazaspiro[4.4]dec-2-ene-5-one;
5(R,S)-3-[2-(piperidin-4-yl)ethyl]-8-(2-carboxyethyl)-1-oxa-2-azaspiro[4.4]deca-2,8-diene-5-one;
5(R,S)-3-[2-(piperidin-4-yl)ethyl]-8-(3-carboxypropyl)-1-oxa-2-azaspiro[4.4]deca-2,8-diene-5-one;
5(R,S)-3-[2-(piperidin-4-yl)ethyl]-8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro[4.4]undec-2-ene-7,9-dione;
5(R,S)-3-[2-(piperidin-4-yl)ethyl]-8-(3-carboxypropyl)-1-oxa-2,8-diazaspiro[4.4]undec-2-ene-7,9-dione;
5(R,S)-3-[2-(piperidin-4-yl)ethyl]-8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro[4.4]undec-2-ene-5-one;
5(R,S)-3-[2-(piperidin-4-yl)ethyl]-8-(3-carboxypropyl)-1-oxa-2,8-diazaspiro[4.4]undec-2-ene-5-one;
5(R,S)-3-[2-(piperidin-4-yl)ethyl]-8-(2-carboxyethyl)-1-oxa-2-azaspiro[4.4]undeca-2,8-diene-5-one;
5(R,S)-3-[2-(piperidin-4-yl)ethyl]-8-(3-carboxypropyl)-1-oxa-2-azaspiro[4.4]undeca-2,8-diene-5-one;
5(R,S)-3-(4-amidinophenyl)-8-[2-(benzyloxycarbonylamino)-2-carboxyethyl]-1-oxa-2,8-diazaspiro[4.5]dec-2-ene.
[20] A fourth embodiment of this invention provides compounds of Formula I: ##STR33## or pharmaceutically acceptable salt or prodrug forms thereof, wherein: R1 is selected from:
R2 (R3)N(CH2)q Z--, R2 (R3)N(R2 N═)C(CH2)q Z--, R2 (R3)N(R2 N═)CN(R2)(CH2)q Z--, piperazinyl-(CH2)q Z-- or ##STR34## Z is selected from O, S, S(═O), S(═O)2 ; R2 and R3 are independently selected from: H, C1 -C10 alkyl, C2 -C6 alkenyl, C3 -C11 cycloalkyl, C4 -C11 cycloalkylalkyl, C6 -C10 aryl, C7 -C11 arylalkyl, C2 -C7 alkylcarbonyl, C7 -C11 arylcarbonyl, C2 -C10 alkoxycarbonyl, C4 -C11 cycloalkoxycarbonyl C7 -C11 bicycloalkoxycarbonyl, C7 -C11 aryloxycarbonyl, or aryl(C1 -C10 alkoxy)carbonyl, C1 -C6 alkylcarbonyloxy(C1 -C4 alkoxy)carbonyl, C6 -C10 arylcarbonyloxy(C1 -C4 alkoxy)carbonyl, C4 -C11 cycloalkylcarbonyloxy (C1 -C4 alkoxy)carbonyl;
U is optionally present and is selected from C1 -C7 alkylene, C2 -C7 alkenylene, C2 -C7 alkynylene, arylene, or pyridylene;
V is selected from:
a single bond (i.e., V is absent);
C1 -C7 alkylene substituted with 0-6 R6 or R7 ;
C2 -C7 alkenylene substituted with 0-4 R6 or R7 ;
C2 -C7 alkynylene substituted with 0-4 R6 or R7 ;
phenylene substituted with 0-4 R6 or R7 ;
pyridylene substituted with 0-3 R6 or R7 ;
pyridazinylene substituted with 0-3 R6 or R7 ;
W is -(aryl)-Z1 -, wherein said aryl is substituted with 0-6 R6 or R7 ;
Z1 is selected from a single bond (i.e., Z1 is absent), --CH2 --, O or S;
X is selected from:
a single bond (i.e., X is absent);
C1 -C7 alkylene substituted with 0-6 R4, R8 or R15 ;
C2 -C7 alkenylene substituted with 0-4 R4, R8 or R15 ;
C2 -C7 alkynylene substituted with 0-4 R4, R8 or R15 ;
Y is selected from hydroxy, C1 to C10 alkyloxy, C3 to C11 cycloalkyloxy, C6 to C10 aryloxy, C7 to C11 aralkyloxy, C3 to C10 alkylcarbonyloxyalkyloxy, C3 to C10 alkoxycarbonyloxyalkyloxy, C2 to C10 alkoxycarbonylalkyloxy, C5 to C10 cycloalkylcarbonyloxyalkyloxy, C5 to C10 cycloalkoxycarbonyloxyalkyloxy, C5 to C10 cycloalkoxycarbonylalkyloxy, C7 to C11 aryloxycarbonylalkyloxy, C8 to C12 aryloxycarbonyloxyalkyloxy, C8 to C12 arylcarbonyloxyalkyloxy, C5 to C10 alkoxyalkylcarbonyloxyalkyloxy, C5 to C10 (5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, C10 to C14 (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy; (R2)(R3)N--(C1 -C10 alkoxy)-;
R4 is selected from H, C1 -C10 alkyl, hydroxy, C1 -C10 alkoxy, nitro, C1 -C10 alkylcarbonyl, or --N(R12)R13 ;
R6 and R7 are each independently selected from H, C1 -C10 alkyl, hydroxy, C1 -C10 alkoxy, nitro, C1 -C10 alkylcarbonyl, --N(R12)R13, cyano, halo, CF3, CHO, CO2 R5a, C(═O)R5a, CONHR5a, CON(R12)2, OC(═O)R5a, OC(═O)OR5a, OR5a, OC(═O)N(R12)2, OCH2 CO2 R5a, CO2 CH2 CO2 R5a, N(R12)2, NO2, NR12 C (═O) R5a, NR12 C(═O)OR5a, NR12 C(═O)N(R12)2, NR12 SO2 N(R12)2, NR12 SO2 R5a, S(O)p R5a, SO2 N(R12)2, C2 to C6 alkenyl, C3 to C11 cycloalkyl, C4 to C11 cycloalkylmethyl;
C6 to C10 aryl optionally substituted with halogen, alkoxy, alkyl, --CF3, S(O)m Me, or --NMe2 ; or
C7 to C11 arylalkyl said aryl being optionally substituted with halogen, alkoxy, alkyl, --CF3, S(O)m Me, or --NMe2 ;
R8 is selected from:
H;
R6 ;
C1 -C10 alkyl, substituted with 0-8 R6 ;
C2 -C10 alkenyl, substituted with 0-6 R6 ;
C2 -C10 alkynyl, substituted with 0-6 R6 ;
C3 -C8 cycloalkyl, substituted with 0-6 R6 ;
C5 -C6 cycloalkenyl, substituted with 0-5 R6 ;
aryl, substituted with 0-5 R6 ;
5-6 membered heterocyclic ring containing 1-2 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-5 R6 ;
R12 and R13 are independently H, C1 -C10 alkyl, C1 -C10 alkoxycarbonyl, C1 -C10 alkylcarbonyl, C1 -C10 alkylsulfonyl, aryl(C1 -C10 alkyl)sulfonyl, arylsulfonyl, aryl, C2 -C6 alkenyl, C3 -C11 cycloalkyl, C4 -C11 cycloalkylalkyl, C7 -C11 arylalkyl, C2 -C7 alkylcarbonyl, C7 -C11 arylcarbonyl, C2 -C10 alkoxycarbonyl, C4 -C11 cycloalkoxycarbonyl, C7 -C11 bicycloalkoxycarbonyl, C7 -C11 aryloxycarbonyl, heteroarylcarbonyl, heteroarylalkylcarbonyl or aryl(C1 -C10 alkoxy)carbonyl;
R14 is selected from H, C1 -C10 alkyl, C2 -C10 alkenyl, C2 -C10 alkynyl, C1 -C10 alkoxy, aryl, heteroaryl or C1 -C10 alkoxycarbonyl, CO2 R5 or --C(═O)N(R12)R13 ;
R5 and R5a are selected independently from H, C1 to C8 alkyl, C2 to C6 alkenyl, C3 to C11 cycloalkyl, C4 to C11 cycloalkylmethyl, C6 to C10 aryl, C7 to C11 arylalkyl, or C1 -C10 alkyl substituted with 0-8 R4 ;
R15 is selected from:
H;
R6 ;
C1 -C10 alkyl, substituted with 6-8 R6 ;
C2 -C10 alkenyl, substituted with 0-6 R6 ;
C1 -C10 alkoxy, substituted with 0-6 R6 ;
aryl, substituted with 0-5 R6 ;
5-6 membered heterocyclic ring containing 1-2 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-5 R6 ;
C1 -C10 alkoxycarbonyl substituted with 0-8 R6 ;
CO2 R5 ; or
--C(═O)N(R12)R13 ;
n is 0-4;
q is 2-7;
r is 0-3;
provided that n, q, and r are chosen such that the number of atoms between R1 and Y is about 8-17.
[21] Preferred compounds of this fourth embodiment are those of Formula IV: ##STR35## wherein: R1 is selected from R2 HN(CH2)q O--, R2 HN(R2 N═C)NH(CH2)q O--, piperazinyl-(CH2)q O--, or ##STR36## Z is O; R2 is selected from H, aryl(C1 -C10)alkoxycarbonyl, C1 -C10 alkoxycarbonyl;
V is selected from:
a single bond (i.e., V is absent);
C1 -C7 alkylene substituted with 0-6 R6 or R7 ;
C2 -C7 alkenylene substituted with 0-4 R6 or R7 ;
C2 -C7 alkynylene substituted with 0-4 R6 or R7 ;
phenylene substituted with 0-3 R6 or R7 ;
pyridylene substituted with 0-3 R6 or R7 ;
pyridazinylene substituted with 0-3 R6 or R7 ;
Z1 is selected from a single bond (i.e., Z1 is absent), O or S;
X is selected from:
a single bond (i.e., X is absent);
C1 -C7 alkylene substituted with 0-4 R4, R8 or R15 ;
C2 -C7 alkenylene substituted with 0-3 R4, R8 or R15 ;
C2 -C7 alkynylene substituted with 0-3 R4, R8 or R15 ;
Y selected from hydroxy, C1 to C10 alkyloxy, C3 to C11 cycloalkyloxy, C6 to C10 aryloxy, C7 to C11 aralkyloxy, C3 to C10 alkylcarbonyloxyalkyloxy, C3 to C10 alkoxycarbonyloxyalkyloxy, C2 to C10 alkoxycarbonylalkyloxy, C5 to C10 cycloalkylcarbonyloxyalkyloxy, C5 to C10 cycloalkoxycarbonyloxyalkyloxy, C5 to C10 cycloalkoxycarbonylalkyloxy, C7 to C11 aryloxycarbonylalkyloxy, C8 to C12 aryloxycarbonyloxyalkyloxy, C8 to C12 arylcarbonyloxyalkyloxy, C5 to C10 alkoxyalkylcarbonyloxyalkyloxy, C5 to C10 (5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, or C10 to C14 (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy;
R4 is selected from H, C1 -C10 alkyl, hydroxy, C1 -C10 alkoxy, nitro, C1 -C10 alkylcarbonyl, or --N(R12)R13 ;
R6 and R7 are selected from H, C1 -C10 alkyl, hydroxy, C1 -C10 alkoxy, nitro, C1 -C10 alkylcarbonyl, --N(R12)R13, cyano, or halo;
R8 is selected from H, C1 -C10 alkyl, C2 -C10 alkenyl, C3 -C8 cycloalkyl, C5 -C6 cycloalkenyl, aryl, 5-6 membered heterocyclic ring containing 1-2 N, O, or S, where said heterocyclic ring may be saturated, partially saturated, or fully unsaturated;
R12 and R13 are independently selected from H, C1 -C10 alkyl, C1 -C10 alkoxycarbonyl, C1 -C10 alkylcarbonyl, C1 -C10 alkylsulfonyl, aryl(C1 -C10 alkyl)sulfonyl, arylsulfonyl, heteroarylcarbonyl, heteroarylalkylcarbonyl or aryl;
R14 is selected from H, C1 -C10 alkyl, C2 -C10 alkenyl, C2 -C10 alkynyl, C1 -C10 alkoxy, aryl, heteroaryl or C1 -C10 alkoxycarbonyl, CO2 R5 or --C(═O)N(R12)R13 ;
R5 is selected from H or C1 -C10 alkyl substituted with 0-6 R4 ;
n is 0-4;
q is 2-7;
provided that n and q are chosen such that the number of atoms between R1 and Y is in the range of 8-17.
[22] Further preferred compounds of this fourth embodiment are compounds of Formula IV wherein:
R1 is R2 HN(CH2)q O-- or ##STR37## V is C1 -C3 alkylene; Z1 is a single bond (i.e. Z1 is absent) or O;
X is C1 -C3 alkylene substituted with 0-1 R4 ;
Y is selected from:
hydroxy;
C1 to C10 alkoxy;
methylcarbonyloxymethoxy-;
ethylcarbonyloxymethoxy-;
t-butylcarbonyloxymethoxy-;
cyclohexylcarbonyloxymethoxy-;
1-(methylcarbonyloxy)ethoxy-;
1-(ethylcarbonyloxy)ethoxy-;
1-(t-butylcarbonyloxy)ethoxy-;
1-(cyclohexylcarbonyloxy)ethoxy-;
i-propyloxycarbonyloxymethoxy-;
t-butyloxycarbonyloxymethoxy-;
1-(i-propyloxycarbonyloxy)ethoxy-;
1-(cyclohexyloxycarbonyloxy)ethoxy-;
1-(t-butyloxycarbonyloxy)ethoxy-;
dimethylaminoethoxy-;
diethylaminoethoxy-;
(5-methyl-1,3-dioxacyclopenten-2-on-4-yl)methoxy-;
(5-(t-butyl)-1,3-dioxacyclopenten-2-on-4-yl)methoxy-;
(1,3-dioxa-5-phenyl-cyclopenten-2-on-4-yl)methoxy-;
1-(2-(2-methoxypropyl)carbonyloxy)ethoxy-;
R12 and R13 are independently selected from H, C1 -C6 alkyl, C1 -C4 alkoxycarbonyl, C1 -C4 alkylcarbonyl, C1 -C6 alkylsulfonyl, aryl(C1 -C4 alkyl)sulfonyl, arylsulfonyl, heteroarylcarbonyl, heteroarylalkylcarbonyl or aryl;
R13 is H.
[23] Specifically preferred compounds of this fourth embodiment are compounds, or pharmaceutically acceptable salt or prodrug forms thereof, selected from:
5(R,S)-4-[3-(piperidin-4-yl)oxymethylisoxazolin-5-yl]hydrocinnamic acid;
5(R,S)-4-[3-(2-aminoethoxymethyl)isoxazolin-5-yl]hydrocinnamic acid;
5(R,S) -4-[3-(3-aminopropyloxymethyl)isoxazolin-5-yl]hydrocinnamic acid;
5(R,S)-4-[3-(piperidin-4-yl)oxymethylisoxazolin-5-yl]phenoxyacetic acid;
5(R,S)-4-[3-(2-aminoethoxymethyl)isoxazolin-5-yl]phenoxyacetic acid;
5(R,S)-4-[3-(3-aminopropyloxymethyl)isoxazolin-5-yl]phenoxyacetic acid.
[24] A fifth embodiment of this invention provides a compound of Formula I: ##STR38## or a pharmaceutically acceptable salt or prodrug form thereof wherein: b is a single or double bond;
R1 is selected from R2a (R3)N--, R2 (R3)N(R2 N═)C--, R2a (R3)N(CH2)q Z--, R2 (R3)N(R2 N═)C(CH2)q Z--, R2 (R3)NC(O)--, R2 (R5 O)N(R2 N═)C--, R2 (R3)N(R5 ON═)C--; ##STR39## Z is selected from a bond (i.e. is absent), O, S, S(═O), S(═O)2 ;
R2 and R3 are independently selected from: H; C1 -C10 alkyl; C3 -C6 alkenyl; C3 -C11 cycloalkyl; C4 -C11 cycloalkylalkyl; C6 -C10 aryl optionally substituted with 0-3 groups selected from hydroxy, halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m CH3, --N(CH3)2, C1 -C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C7 -C11 arylalkyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m CH3, --N(CH3)2, C1 -C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C2 -C7 alkylcarbonyl; C7 -C11 arylcarbonyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m CH3, --N(CH3)2, C1 -C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C1 -C10 alkoxycarbonyl; C4 -C11 cycloalkoxycarbonyl; C7 -C11 bicycloalkoxycarbonyl; C7 -C11 aryloxycarbonyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m CH3, --N(CH3)2, C1 -C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; aryl(C1 -C10 alkoxy)carbonyl where the aryl group is optionally substituted with 0-3 groups selected from hydroxy, halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m CH3, --N(CH3)2, C1 -C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C1 -C6 alkylcarbonyloxy(C1 -C4 alkoxy)carbonyl; C6 -C10 arylcarbonyloxy(C1 -C4 alkoxy)carbonyl where the aryl group is optionally substituted with 0-3 groups selected from hydroxy, halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m CH3, --N(CH3)2, C1 -C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C4 -C11 cycloalkylcarbonyloxy(C1 -C4 alkoxy)carbonyl; heteroaryl optionally substituted with 0-2 groups selected from hydroxy, halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m CH3, --N(CH3)2, C1 -C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; or heteroaryl(C1 -C5)alkyl where the heteroaryl group is optionally substituted with 0-2 groups selected from hydroxy, halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m CH3, --N(CH3)2, C1 -C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl;
provided that only one of R2 and R3 may be hydroxy;
R2a is R2 or R2 (R3)N(R2 N═)C;
U is selected from:
a single bond (i.e., U is not present),
--(C1 -C7 alkyl)-,
--(C2 -C7 alkenyl)-,
--(C2 -C7 alkynyl)-,
-(aryl)-substituted with 0-3 R6a, or
-(pyridyl)-substituted with 0-3 R6a ;
V is selected from:
a single bond (i.e., V is not present);
--(C1 -C7 alkyl)-, substituted with 0-3 groups independently selected from R6 or R7 ;
--(C2 -C7 alkenyl)-, substituted with 0-3 groups independently selected from R6 or R7 ;
--(C2 -C7 alkynyl)-, substituted with 0-3 groups independently selected from R6 or R7 ;
-(phenyl)-, substituted with 0-2 groups independently selected from R6 or R7 ;
-(pyridyl)-, substituted with 0-2 groups independently selected from R6 or R7 ; or
-(pyridazinyl)-, substituted with 0-2 groups independently selected from R6 or R7 ;
W is selected from: ##STR40## X is selected from: a single bond (i.e. X is absent) --(C(R4)2)n --C(R4)(R8)--C(R4)(R4a)--, with the proviso that when n is 0 or 1, then at least one of R4a or R8 is other than H or methyl;
Y is selected from:
hydroxy,
C1 to C10 alkyloxy,
C3 to C11 cycloalkyloxy,
C6 to C10 aryloxy,
C7 to C11 aralkyloxy,
C3 to C10 alkylcarbonyloxyalkyloxy,
C3 to C10 alkoxycarbonyloxyalkyloxy,
C2 to C10 alkoxycarbonylalkyloxy,
C5 to C10 cycloalkylcarbonyloxyalkyloxy,
C5 to C10 cycloalkoxycarbonyloxyalkyloxy.
C5 to C10 cycloalkoxycarbonylalkyloxy,
C7 to C11 aryloxycarbonylalkyloxy,
C7 to C12 aryloxycarbonyloxyalkyloxy,
C8 to C12 arylcarbonyloxyalkyloxy,
C5 to C10 alkoxyalkylcarbonyloxyalkyloxy,
C5 to C10 (5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy,
C10 to C14 (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy,
(R2)(R3)N--(C1 -C10 alkoxy)-;
Z1 is --C--, --O--, or --NR22 --;
Z2 is --O--, or --NR22 --;
R4 is selected from H, C1 -C10 alkyl, C1 -C10 alkylcarbonyl, aryl, arylalkylene cycloalkyl, or cycloalkylalkylene;
alternately, two R4 groups on adjacent carbons may join to form a bond (i.e. a carbon--carbon double or triple bond);
R4a is selected from H, hydroxy, C1 -C10 alkoxy, nitro, N(R5)R5a, --N(R12)R13, --N(R16)R17, C1 -C10 alkyl substituted with 0-3 R6, aryl substituted with 0-3 R6, or C1 -C10 alkylcarbonyl;
R4b is selected from H, C1 -C6 alkyl, C2 -C6 alkenyl, C2 -C6 alkynyl, hydroxy, C1 -C6 alkoxy, C1 -C6 alkylthio, C1 -C6 alkylsulfinyl, C1 -C6 alkylsulfonyl, nitro, C1 -C6 alkylcarbonyl, C6 -C10 aryl, --N(R12)R13 ; halo, CF3, CN, C1 -C6 alkoxycarbonyl, carboxy, piperidinyl, or pyridyl;
R5 is selected from H, C1 -C8 alkyl, C2 -C6 alkenyl, C3 -C11 cycloalkyl, C4 -C11 cycloalkylmethyl, C6 -C10 aryl, C7 -C11 arylalkyl, or C1 -C10 alkyl substituted with 0-2 R4b ;
R5a is selected from hydrogen, hydroxy, C1 to C8 alkyl, C2 to C6 alkenyl, C3 to C11 cycloalkyl, C4 to C11 cycloalkylmethyl, C1 -C6 alkoxy, benzyloxy, C6 to C10 aryl, heteroaryl, C7 to C11 arylalkyl, or C1 -C10 alkyl substituted with 0-2 R4b ;
alternately, R5 and R5a when both are substituents on the same nitrogen atom (as in --NR5 R5a) can be taken together with the nitrogen atom to which they are attached to form 3-azabicyclononyl, 1,2,3,4-tetrahydro-1-quinolinyl, 1,2,3,4-tetrahydro-2-isoquinolinyl, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl or 1-piperazinyl, each being optionally substituted with C1 -C6 alkyl, C6 -C10 aryl, heteroaryl, C7 -C11 arylalkyl, C1 -C6 alkylcarbonyl, C3 -C7 cycloalkylcarbonyl, C1 -C6 alkoxycarbonyl, C7 -C11 arylalkoxycarbonyl, C1 -C6 alkylsulfonyl or C6 -C10 arylsulfonyl;
R5b is selected from C1 -C8 alkyl, C2 -C6 alkenyl, C3 -C11 cycloalkyl, C4 -C11 cycloalkylmethyl, C6 -C10 aryl, C7 -C11 arylalkyl, or C1 -C10 alkyl substituted with 0-2 R4b ;
R6 is selected from H, C1 -C10 alkyl, hydroxy, C1 -C10 alkoxy, nitro, C1 -C10 alkylcarbonyl, --N(R12)R13, cyano, halo, CF3, CHO, CO2 R5, C(═O)R5a, CONR5 R5a, OC(═O)R5a, OC(═O)OR5b, OR5, OC(═O)NR5 R5a, OCH2 CO2 R5, CO2 CH2 CO2 R5, NO2, NR5a C(═O)R5a, NR5a C(═O)OR5b, NR5a C(═O)NR5 R5a, NR5a SO2 NR5 R5a, NR5a SO2 R5, S(O)p R5, SO2 NR5 R5a, C2 to C6 alkenyl, C3 to C11 cycloalkyl, C4 to C11 cycloalkylmethyl;
C6 to C10 aryl optionally substituted with 1-3 groups selected from halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m Me, or --NMe2 ;
C7 to C11 arylalkyl, said aryl being optionally substituted with 1-3 groups selected from halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m Me, or --NMe2 ;
methylenedioxy when R6 is a substiuent on aryl; or
a 5-6 membered heterocyclic ring containing 1-2 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R7 ;
R6a is selected from C1 -C4 alkyl, C1 -C4 alkoxy, halo, CF3, NO2, or NR12 R13 ;
R7 is selected from H, C1 -C10 alkyl, hydroxy, C1 -C10 alkoxy, nitro, C1 -C10 alkylcarbonyl, --N(R12)R13, cyano, halo, CF3, CHO, CO2 R5, C(═O)R5a, CONR5 R5a, OC(═O)R5a, OC(═O)OR5b, OR5a, OC(═O)NR5 R5a, OCH2 CO2 R5, CO2 CH2 CO2 R5, NO2, NR5a C(═O)R5a, NR5a C(═O)OR5b, NR5a C(═O)NR5 R5a, NR5a SO2 NR5 R5a, NR5a SO2 R5, S(O)m R5a, SO2 NR5 R5a, C2 to C6 alkenyl, C3 to C11 cycloalkyl, C4 to C11 cycloalkylmethyl, C6 to C10 aryl, or C7 to C11 arylalkyl;
R8 is selected from:
R6 ;
C2 -C10 alkyl, substituted with 0-3 R6 ;
C2 -C10 alkenyl, substituted with 0-3 R6 ;
C2 -C10 alkynyl, substituted with 0-3 R6 ;
C3 -C8 cycloalkyl, substituted with 0-3 R6 ;
C5 -C6 cycloalkenyl, substituted with 0-3 R6 ;
aryl, substituted with 0-3 R6 ;
5-6 membered heterocyclic ring containing 1-2 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R6 ;
R12 and R13 are independently H, C1 -C10 alkyl, C1 -C10 alkoxycarbonyl, C1 -C10 alkylcarbonyl, C1 -C10 alkylsulfonyl, aryl(C1 -C10 alkyl)sulfonyl, arylsulfonyl, aryl, C2 -C6 alkenyl, C3 -C11 cycloalkyl, C4 -C11 cycloalkylalkyl, C7 -C11 arylalkyl, C7 -C11 arylcarbonyl, C4 -C11 cycloalkoxycarbonyl, C7 -C11 bicycloalkoxycarbonyl, C7 -C11 aryloxycarbonyl, or aryl(C1 -C10 alkoxy)carbonyl, wherein said aryls are optionally substituted with 0-3 substituents selected from the group consisting of: C1 -C4 alkyl, C1 -C4 alkoxy, halo, CF3, and NO2 ;
R14 is selected from H, C1 -C10 alkyl, C2 -C10 alkenyl, C2 -C10 alkynyl, C1 -C10 alkoxy, aryl, heteroaryl or C1 -C10 alkoxycarbonyl, CO2 R5 or --C(═O)N(R5)R5a ;
R15 is selected from:
H;
R6 ;
C1 -C10 alkyl, substituted with 0-3 R6 ;
C2 -C10 alkenyl, substituted with 0-3 R6 ;
C1 -C10 alkoxy, substituted with 0-3 R6 ;
aryl, substituted with 0-3 R6 ;
5-6 membered heterocyclic ring containing 1-2 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R6 ;
C1 -C10 alkoxycarbonyl substituted with 0-2 R6 ;
-CO2 R5 ; or
--C(═O)N(R12)R13 ;
provided that when b is a double bond, only one of R14 or R15 is present;
R16 is selected from:
--C(═O)--O--R18a,
--C(═O)--R18b,
--C(═O)N(R18b)2,
--C(═O)NHSO2 R18a,
--C(═O)NHC(═O)R18b,
--C(═O)NHC(═O)OR18a,
--C(═O)NHSO2 NHR18b,
--C(═S)--NH--R18b,
--NH--C(═O)--O--R18a,
--NH--C(═O)--R18b,
--NH--C(═O)--NH--R18b,
--SO2 --O--R18a,
--SO2 --R18a,
--SO2 --N(18b)2,
--SO2 --NHC(═O)O18b,
--P(═S)(OR18a)2,
--P(═O)(OR18a)2,
--P(═S)(R18a)2,
--P(═O)(R18a)2, or ##STR41## R17 is selected from: H, C1 -C10 alkyl, C2 -C6 alkenyl, C3 -C11 cycloalkyl, C4 -C15 cycloalkylalkyl, aryl, aryl(C1 -C10 alkyl)-;
R18a is selected from:
C1 -C8 alkyl substituted with 0-2 R19,
C2 -C8 alkenyl substituted with 0-2 R19,
C2 -C8 alkynyl substituted with 0-2 R19,
C3 -C8 cycloalkyl substituted with 0-2 R19,
aryl substituted with 0-4 R19,
aryl(C1 -C6 alkyl)-substituted with 0-4 R19,
a 5-10 membered heterocyclic ring system having 1-3 heteroatoms selected independently from O, S, and N, said heterocyclic ring being substituted with 0-4 R19,
C1 -C6 alkyl substituted with a 5-10 membered heterocyclic ring system having 1-3 heteroatoms selected independently from O, S, and N, said heterocyclic ring being substituted with 0-4 R19 ;
R18b is selected from R18a or H;
R19 is selected from H, halogen, CF3, CN, NO2, NR12 R13, C1 -C8 alkyl, C2 -C6 alkenyl, C2 -C6 alkynyl, C3 -C11 cycloalkyl, C4 -C11 cycloalkylalkyl, aryl, aryl(C1 -C6 alkyl)-, C1 -C6 alkoxy, or C1 -C4 alkoxycarbonyl;
R20 and R21 are each independently selected from H, C1 -C10 alkyl, CO2 R5, C(═O)R5a, CONR5 R5a, NR5 C(═O)R5a, NR12 R13, C2 -C6 alkenyl, C3 -C11 cycloalkyl, C4 -C11 cycloalkylmethyl, C6 -C10 aryl, or C7 -C11 arylalkyl;
R22 is selected from C1 -C10 alkyl, C2 -C6 alkenyl, C3 -C11 cycloalkyl, C4 -C15 cycloalkylalkyl, aryl, aryl (C1 -C10 alkyl)-; C(═O)R5a, CO2 R5b, --C(═O)N(R5)R5a, or a bond to X;
m is 0-2;
n is 0-2;
p is 1-2;
q is 1-7;
r is 0-3;
provided that n, q and r are chosen such that the number of atoms connecting R1 and Y is in the range of 8-17.
[25] Preferred compounds of this embodiment are those compounds of Formula Ic: ##STR42## wherein: Z is selected from a bond (i.e. is absent), O, or S;
R2 and R3 are independently selected from: H; C1 -C6 alkyl; C7 -C11 arylalkyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m CH3, --N(CH3)2, C1 -C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C1 -C10 alkoxycarbonyl; aryl(C1 -C10 alkoxy)carbonyl where the aryl group is optionally substituted with 0-3 groups selected from hydroxy, halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m CH3, --N(CH3)2, C1 -C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; or heteroaryl(C1 -C5)alkyl where the heteroaryl group is optionally substituted with 0-2 groups selected from hydroxy, halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m CH3, --N(CH3)2, C1 -C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl;
U is a single bond (i.e., U is not present);
X is --CHR4a --;
R5 is selected from H or C1 -C10 alkyl substituted with 0-6 R4b ;
R6 and R7 are each independently selected from H, C1 -C10 alkyl, hydroxy, C1 -C10 alkoxy, nitro, C1 -C10 alkylcarbonyl, --N(R12)R13, cyano, or halo;
R12 and R13 are each independently selected from H, C1 -C10 alkyl, C1 -C10 alkoxycarbonyl, C1 -C10 alkylcarbonyl, C1 -C10 alkylsulfonyl, aryl(C1 -C10 alkyl)sulfonyl, arylsulfonyl, or aryl, wherein said aryls are optionally substituted with 0-3 substituents selected from the group consisting of: C1 -C4 alkyl, C1 -C4 alkoxy, halo, CF3, and NO2 ;
R15 is selected from H, C1 -C10 alkyl, C2 -C10 alkenyl, C2 -C10 alkynyl, C1 -C10 alkoxy, aryl, heteroaryl or C1 -C10 alkoxycarbonyl, CO2 R5 or --C(═O)N(R5)R5a ;
R16 is selected from:
--C(═O)--O--R18a,
--C(═O)--R18b,
--S(═O)2 --R18a ;
R17 is selected from: H or C1 -C4 alkyl;
R18a is selected from:
C1 -C8 alkyl substituted with 0-2 R19,
C2 -C8 alkenyl substituted with 0-2 R19,
C2 -C8 alkynyl substituted with 0-2 R19,
C3 -C8 cycloalkyl substituted with 0-2 R19,
aryl substituted with 0-2 R19,
aryl(C1 -C6 alkyl)-substituted with 0-2 R19,
a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, isoxazolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyridinyl, 3H-indolyl, carbazolyl, pyrrolidinyl, piperidinyl, indolinyl, or morpholinyl, said heterocyclic ring being substituted with 0-2 R19 ;
C1 -C6 alkyl substituted with a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolinyl, benzofuranyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyridinyl, 3H-indolyl, indolyl, carbazole, pyrrolidinyl, piperidinyl, indolinyl, or morpholinyl, said heterocyclic ring being substituted with 0-2 R19.
[26] Further preferred compounds of this embodiment are compounds of Formula Ib: ##STR43## wherein: R1 is selected from: R2 (R3)N--, R2 NH(R2 N═)C--, R2 R3 N(CH2)p" Z--, R2 NH(R2 N═)CNH(CH2)p' Z--, R2 (R3)NC(O)--, R2 (R5 O)N(R2 N═)C--, R2 (R3)N(R5 ON═)C--; ##STR44## n is 0-1; p' is 2-4;
p" is 4-6;
Z is selected from a bond (i.e. is absent) or O;
R3 is H or C1 -C5 alkyl;
V is a single bond (i.e., V is not present), or -(phenyl)-;
X is selected from:
--CH2 --,
--CHN(R16)R17 --, or
CHNR5 R5a --;
Y is selected from:
hydroxy;
C1 to C10 alkoxy;
methylcarbonyloxymethoxy-;
ethylcarbonyloxymethoxy-;
t-butylcarbonyloxymethoxy-;
cyclohexylcarbonyloxymethoxy-;
1-(methylcarbonyloxy)ethoxy-;
1-(ethylcarbonyloxy)ethoxy-;
1-(t-butylcarbonyloxy)ethoxy-;
1-(cyclohexylcarbonyloxy)ethoxy-;
i-propyloxycarbonyloxymethoxy
t-butyloxycarbonyloxymethoxy-;
1-(i-propyloxycarbonyloxy)ethoxy-;
1-(cyclohexyloxycarbonyloxy)ethoxy-;
1-(t-butyloxycarbonyloxy)ethoxy-;
dimethylaminoethoxy-;
diethylaminoethoxy-;
(5-methyl-1,3-dioxacyclopenten-2-on-4-yl)methoxy-;
(5-(t-butyl)-1,3-dioxacyclopenten-2-on-4-yl)methoxy-;
(1,3-dioxa-5-phenyl-cyclopenten-2-on-4-yl)methoxy-;
1-(2-(2-methoxypropyl)carbonyloxy)ethoxy-;
R18a is selected from:
C1 -C4 alkyl substituted with 0-2 R19,
C2 -C4 alkenyl substituted with 0-2 R19,
C2 -C4 alkynyl substituted with 0-2 R19,
C3 -C4 cycloalkyl substituted with 0-2 R19,
aryl substituted with 0-2 R19,
aryl(C1 -C4 alkyl)-substituted with 0-2 R19,
a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, isoxazolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyridinyl, 3H-indolyl, carbazolyl, pyrrolidinyl, piperidinyl, indolinyl, or morpholinyl, said heterocyclic ring being substituted with 0-2 R19 ;
C1 -C6 alkyl substituted with a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolinyl, benzofuranyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyridinyl, 3H-indolyl, indolyl, carbazole, pyrrolidinyl, piperidinyl, indolinyl, or morpholinyl, said heterocyclic ring being substituted with 0-2 R19.
[27] Further preferred compounds of this fifth embodiment are compounds of Formula Ib wherein:
R1 is R2 NH(R2 N═)C-- or R2 NH(R2 N═)CNH-- and V is phenyl or pyridyl; or
R1 is ##STR45## and V is a single bond (i.e. V is absent) n is 1-2;
X is selected from:
--CH2 --,
--CHN(R16)R17 --, or
--CHNR5 R5a --;
W is selected from: ##STR46## m is 1-3; Y is selected from:
hydroxy;
C1 to C10 alkoxy;
methylcarbonyloxymethoxy-;
ethylcarbonyloxymethoxy-;
t-butylcarbonyloxymethoxy-;
cyclohexylcarbonyloxymethoxy-;
1-(methylcarbonyloxy)ethoxy-;
1-(ethylcarbonyloxy)ethoxy-;
1-(t-butylcarbonyloxy)ethoxy-;
1-(cyclohexylcarbonyloxy)ethoxy-;
i-propyloxycarbonyloxymethoxy-;
t-butyloxycarbonyloxymethoxy-;
1-(i-propyloxycarbonyloxy)ethoxy-;
1-(cyclohexyloxycarbonyloxy)ethoxy-;
1-(t-butyloxycarbonyloxy)ethoxy-;
dimethylaminoethoxy-;
diethylaminoethoxy-;
(5-methyl-1,3-dioxacyclopenten-2-on-4-yl)methoxy-;
(5-(t-butyl)-1,3-dioxacyclopenten-2-on-4-yl)methoxy-;
(1,3-dioxa-5-phenyl-cyclopenten-2-on-4-yl)methoxy-;
1-(2-(2-methoxypropyl)carbonyloxy)ethoxy-;
R19 is H, halogen, C1 -C4 alkyl, C3 -C7 cycloalkyl, cyclopropylmethyl, aryl, or benzyl;
R20 and R21 are both H;
R22 is H, C1 -C4 alkyl or benzyl.
[28] Specifically preferred compounds of this fifth embodiment are compounds of Formula Ib, or pharmaceutically acceptable salt forms thereof, selected from:
2-(R,S)-2-carboxymethyl-1-{5-(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-yl acetyl]piperidine;
2-(R,S)-2-carboxymethyl-1-{5-(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-yl acetyl]azepine;
2-(R,S)-2-carboxymethyl-1-{5-(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-yl acetyl]pyrrolidine;
3-(R,S)-carboxymethyl-4-{5-(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-yl acetyl]piperazine-2-one;
6-(R,S)-carboxymethyl-1-{5-(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-yl acetyl]piperidine-2-one;
5-(R,S)-carboxymethyl-1-{5-(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-yl acetyl]pyrrolidine-2-one;
7-(R,S)-carboxymethyl-1-{5-(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-yl acetyl]azetidine-2-one;
2-(R,S) -carboxymethyl-1-{5-(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-yl acetyl]pyrazolidine;
3-(R,S)-carboxymethyl-4-{5-(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-yl acetyl]morpholine.
In the present invention it has been discovered that the compounds of Formula I above are useful as inhibitors of cell-matrix and cell--cell adhesion processes. The present invention includes novel compounds of Formula I and methods for using such compounds for the prevention or treatment of diseases resulting from abnormal cell adhesion to the extracellular matrix which comprises administering to a host in need of such treatment a therapeutically effective amount of such compound of Formula I.
In the present invention it has also been discovered that the compounds of Formula I above are useful as inhibitors of glycoprotein IIb/IIIa (GPIIb/IIIa). The compounds of the present invention inhibit the activation and aggregation of platelets induced by all known endogenous platelet agonists.
The present invention also provides pharmaceutical compositions comprising a compound of Formula I and a pharmaceutically acceptable carrier.
The compounds of Formula I of the present invention are useful for the treatment (including prevention) of thromboembolic disorders. The term "thromboembolic disorders" as used herein includes conditions involving platelet activation and aggregation, such as arterial or venous cardiovascular or cerebrovascular thromboembolic disorders, including, for example, thrombosis, unstable angina, first or recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary and cerebral arterial thrombosis, myocardial infarction, cerebral embolism, kidney embolisms, pulmonary embolisms, or such disorders associated with diabetes, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Formula I described above.
The compounds of Formula I of the present invention may be useful for the treatment or prevention of other diseases which involve cell adhesion processes, including, but not limited to, infammation, bone degradation, rheumatoid arthritis, asthma, allergies, adult respiratory distress syndrome, graft versus host disease, organ transplantation rejection, septic shock, psoriasis, eczema, contact dermatitis, osteoporosis, osteoarthritis, atherosclerosis, tumors, metastasis, diabetic retinopathy, inflammatory bowel disease and other autoimmune diseases. The compounds of Formula I of the present invention may also be useful for wound healing.
The compounds of the present invention are useful for inhibiting the binding of fibrinogen to blood platelets, inhibiting aggregation of blood platelets, treating thrombus formation or embolus formation, or preventing thrombus or embolus formation in a mammal. The compounds of the invention may be used as a medicament for blocking fibrinogen from acting at its receptor site in a mammal.
Compounds of the invention may be administered to patients where prevention of thrombosis by inhibiting binding of fibrinogen to the platelet membrane glycoprotein complex IIb/IIIa receptor is desired. They are useful in surgery on peripheral arteries (arterial grafts, carotid endarterectomy) and in cardiovascular surgery where manipulation of arteries and organs, and/or the interaction of platelets with artificial surfaces, leads to platelet aggregation and consumption, and where the aggregated platelets may form thrombi and thromboemboli. The compounds of the present invention may be administered to these surgical patients to prevent the formation of thrombi and thromboemboli.
Extracorporeal circulation is routinely used during cardiovascular surgery in order to oxygenate blood. Platelets adhere to surfaces of the extracorporeal circuit. Adhesion is dependent on the interaction between GPIIb/IIIa on the platelet membranes and fibrinogen adsorbed to the surface of the extracorporeal circuit. Platelets released from artificial surfaces show impaired homeostatic function. The compounds of the invention may be administered to prevent such ex vivo adhesion.
The compounds of the present invention may be used for other ex vivo applications to prevent cellular adhesion in biological samples.
Other applications of these compounds include prevention of platelet thrombosis, thromboembolism, and reocclusion during and after thrombolytic therapy and prevention of platelet thrombosis, thromboembolism and reocclusion after angioplasty of coronary and other arteries and after coronary artery bypass procedures. The compounds of the present invention may also be used to prevent myocardial infarction. The compounds of the present invention are useful as thrombolytics for the treatment of thromboembolic disorders.
The compounds of the present invention can also be administered in combination with one or more additional therapeutic agents select from: anti-coagulant or coagulation inhibitory agents, such as heparin or warfarin; anti-platelet or platelet inhibitory agents, such as aspirin, piroxicam, or ticlopidine; thrombin inhibitors such as boropeptides, hirudin or argatroban; or thrombolytic or fibrinolytic agents, such as plasminogen activators, anistreplase, urokinase, or streptokinase.
The compounds of Formula I of the present invention can be administered in combination with one or more of the foregoing additional therapeutic agents, thereby to reduce the doses of each drug required to achieve the desired therapeutic effect. Thus, the combination treatment of the present invention permits the use of lower doses of each component, with reduced adverse, toxic effects of each component. A lower dosage minimizes the potential of side effects of the compounds, thereby providing an increased margin of safety relative to the margin of safety for each component when used as a single agent. Such combination therapies may be employed to achieve synergistic or additive therapeutic effects for the treatment of thromboembolic disorders.
By "therapeutically effective amount" it is meant an amount of a compound of Formula I that when administered alone or in combination with an additional therapeutic agent to a cell or mammal is effective to prevent or ameliorate the thromboembolic disease condition or the progression of the disease.
By "administered in combination" or "combination therapy" it is meant that the compound of Formula I and one or more additional therapeutic agents are administered concurrently to the mammal being treated. When administered in combination each component may be administered at the same time or sequentially in any order at different points in time. Thus, each component may be administered separately but sufficiently closely in time so as to provide the desired therapeutic effect.
The term anti-coagulant agents (or coagulation inhibitory agents), as used herein, denotes agents that inhibit blood coagulation. Such agents include warfarin (available as Coumadin™) and heparin.
The term anti-platelet agents (or platelet inhibitory agents), as used herein, denotes agents that inhibit platelet function such as by inhibiting the aggregation, adhesion or granular secretion of platelets. Such agents include the various known non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone, and piroxicam, including pharmaceutically acceptable salts or prodrugs thereof. Of the NSAIDS, aspirin (acetylsalicyclic acid or ASA), and piroxicam. Piroxicam is commercially available from Pfizer Inc. (New York, N.Y.), as Feldane™. Other suitable anti-platelet agents include ticlopidine, including pharmaceutically acceptable salts or prodrugs thereof. Ticlopidine is also a preferred compound since it is known to be gentle on the gastro-intestinal tract in use. Still other suitable platelet inhibitory agents include thromboxane-A2-receptor antagonists and thromboxane-A2-synthetase inhibitors, as well as pharmaceutically acceptable salts or prodrugs thereof.
The phrase thrombin inhibitors (or anti-thrombin agents), as used herein, denotes inhibitors of the serine protease thrombin and other inhibitors of thrombin synthesis such as Factor XA. By inhibiting thrombin, various thrombin-mediated processes, such as thrombin-mediated platelet activation (that is, for example, the aggregation of platelets, and/or the granular secretion of plasminogen activator inhibitor-1 and/or serotonin) and/or fibrin formation are disrupted. Such inhibitors include boroarginine derivatives and boropeptides, hirudin and argatroban, including pharmaceutically acceptable salts and prodrugs thereof. Boroarginine derivatives and boropeptides include N-acetyl and peptide derivatives of boronic acid, such as C-terminal α-aminoboronic acid derivatives of lysine, ornithine, arginine, homoarginine and corresponding isothiouronium analogs thereof. The term hirudin, as used herein, includes suitable derivatives or analogs of hirudin, referred to herein as hirulogs, such as disulfatohirudin. Boropeptide thrombin inhibitors include compounds described in Kettner et al., U.S. Pat. No. 5,187,157 and European Patent Application Publication Number 293 881 A2, the disclosures of which are hereby incorporated herein by reference. Other suitable boroarginine derivatives and boropeptide thrombin inhibitors include those disclosed in PCT Application Publication Number 92/07869 and European Patent Application Publication Number 471 651 A2, the disclosures of which are hereby incorporated herein by reference, in their entirety.
The phrase thrombolytics (or fibrinolytic) agents (or thrombolytics or fibrinolytics), as used herein, denotes agents that lyse blood clots (thrombi). Such agents include tissue plasminogen activator, anistreplase, urokinase or streptokinase, including pharmaceutically acceptable salts or prodrugs thereof. Tissue plasminogen activator (tPA) is commercially available from Genentech Inc., South San Francisco, Calif. The term anistreplase, as used herein, refers to anisoylated plasminogen streptokinase activator complex, as described, for example, in European Patent Application No. 028,489, the disclosures of which are hereby incorporated herein by reference herein, in their entirety. Anistreplase is commercially available as Eminase™. The term urokinase, as used herein, is intended to denote both dual and single chain urokinase, the latter also being referred to herein as prourokinase.
Administration of the compounds of Formula I of the invention in combination with such additional therapeutic agent, may afford an efficacy advantage over the compounds and agents alone, and may do so while permitting the use of lower doses of each. A lower dosage minimizes the potential of side effects, thereby providing an increased margin of safety.
GPIIb/IIIa is known to be overexpressed in metastatic tumor cells. The compounds or combination products of the present invention may also be useful for the treatment, including prevention, of metastatic cancer.
The compounds of the present invention are also useful as standard or reference compounds, for example as a quality standard or control, in tests or assays involving the binding of fibrinogen to platelet GPIIb/IIIa. Such compounds may be provided in a commercial kit, for example, for use in pharmaceutical research involving GPIIb/IIIa. The compounds of the present invention may also be used in diagnostic assays involving platelet GPIIb/IIIa.
The compounds herein described may have asymmetric centers. Unless otherwise indicated, all chiral, diastereomeric and racemic forms are included in the present invention. Many geometric isomers of olefins, C═N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. It will be appreciated that compounds of the present invention that contain asymmetrically substituted carbon atoms may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis, from optically active starting materials. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated.
When any variable (for example but not limited to, R2, R4, R6, R7, R8, R12, and R14, n, etc.) occurs more than one time in any constituent or in any formula, its definition on each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R4, then said group may optionally be substituted with up to two R4 and R4 at each occurrence is selected independently from the defined list of possible R4. Also, by way of example, for the group --N(R5a)2, each of the two R5a substituents on N is independently selected from the defined list of possible R5a. Similarly, by way of example, for the group --C(R7)2 --, each of the two R7 substituents on C is independently selected from the defined list of possible R7.
When a bond to a substituent is shown to cross the bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a bond joining a substituent to another group is not specifically shown or the atom in such other group to which the bond joins is not specifically shown, then such substituent may form a bond with any atom on such other group.
When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of Formula I, then such substituent may be bonded via any atom in such substituent. For example, when the substituent is piperazinyl, piperidinyl, or tetrazolyl, unless specified otherwise, said piperazinyl, piperidinyl, tetrazolyl group may be bonded to the rest of the compound of Formula I via any atom in such piperazinyl, piperidinyl, tetrazolyl group.
Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By stable compound or stable structure it is meant herein a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
The term "substituted", as used herein, means that any one or more hydrogen on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substitent is keto (i.e., ═O), then 2 hydrogens on the atom are replaced.
As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms (for example, "C1 -C10 " denotes alkyl having 1 to 10 carbon atoms); "haloalkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example --Cv Fw where v=1 to 3 and w=1 to (2v+1)); "alkoxy" represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge; "cycloalkyl" is intended to include saturated ring groups, including mono-, bi-, or poly-cyclic ring systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and adamantyl; and "bicycloalkyl" is intended to include saturated bicyclic ring groups such as [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, and so forth. "Alkenyl" is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon--carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl and the like; and "alkynyl" is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbon--carbon bonds which may occur in any stable point along the chain, such as ethynyl, propynyl and the like.
The terms "alkylene", "alkenylene", "phenylene", and the like, refer to alkyl, alkenyl, and phenyl groups, respectively, which are connected by two bonds to the rest of the structure of Formula I. Such "alkylene", "alkenylene", "phenylene", and the like, may alternatively and equivalently be denoted herein as "-(alkyl)-", "-(alkenyl)-" and "-(phenyl)-", and the like.
"Halo" or "halogen" as used herein refers to fluoro, chloro, bromo and iodo; and "counterion" is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate and the like.
As used herein, "aryl" or "aromatic residue" is intended to mean phenyl or naphthyl optionally substituted with 0-3 groups independently selected from methyl, methoxy, amino, hydroxy, halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m CH3, --N(CH3)2, C1 -C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; the term "arylalkyl" represents an aryl group attached through an alkyl bridge.
As used herein, "carbocycle" or "carbocyclic residue" is intended to mean any stable 3- to 7-membered monocyclic or bicyclic or 7- to 14-membered bicyclic or tricyclic or an up to 26-membered polycyclic carbon ring, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocyles include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, biphenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).
As used herein, the term "heterocycle" or "heterocyclic" is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic ring which may be saturated, partially unsaturated, or aromatic, and which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. Examples of such heterocycles include, but are not limited to, pyridyl (pyridinyl), pyrimidinyl, furanyl (furyl), thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, benzothiophenyl, indolyl, indolenyl, isoxazolinyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl or octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazolyl, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazole, carbazole, β-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, phenarsazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl or oxazolidinyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
As used herein, the term "heteroaryl" refers to aromatic heterocyclic groups. Such heteroaryl groups are preferably 5-6 membered monocylic groups or 8-10 membered fused bicyclic groups. Examples of such heteroaryl groups include, but are not limited to pyridyl (pyridinyl), pyrimidinyl, furanyl (furyl), thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, indolyl, isoxazolyl, oxazolyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothienyl, benzimidazolyl, quinolinyl, or isoquinolinyl.
As used herein, the term "chiral amine" refers to any amine containing compound that also contains a chiral center. Such compounds include, by way of example and without limitation, either enantiomer of cinchonidine, ephedrine, 2-phenylglycinol, 2-amino-3-methoxy-1-propanol, quinidine and pseudoephedrine.
As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound of Formula I is modified by making acid or base salts of the compound of Formula I. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
"Prodrugs" are considered to be any covalently bonded carriers which release the active parent drug according to Formula I in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the compounds of Formula I are prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds. Prodrugs include compounds of Formula I wherein hydroxyl, amino, sulfhydryl, or carboxyl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, sulfhydryl, or carboxyl group respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of Formula I, and the like. Examples of representative carboxyl and amino prodrugs are included under the definition of R2, R3, and Y.
The pharmaceutically acceptable salts of the compounds of Formula I include the conventional non-toxic salts or the quaternary ammonium salts of the compounds of Formula I formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
The pharmaceutically acceptable salts of the present invention can be synthesized from the compounds of Formula I which contain a basic or acidic moiety by conventional chemical methods. Generally, the salts are prepared by reacting the free base or acid with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid or base in a suitable solvent or various combinations of solvents.
The pharmaceutically acceptable salts of the acids of Formula I with an appropriate amount of a base, such as an alkali or alkaline earth metal hydroxide e.g. sodium, potassium, lithium, calcium, or magnesium, or an organic base such as an amine, e.g., dibenzylethylenediamine, trimethylamine, piperidine, pyrrolidine, benzylamine and the like, or a quaternary ammonium hydroxide such as tetramethylammoinum hydroxide and the like.
As discussed above, pharmaceutically acceptable salts of the compounds of the invention can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid, respectively, in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.; 1985; p. 1418, the disclosure of which is hereby incorporated by reference.
The disclosures of all of the references cited herein are hereby incorporated herein by reference in their entirety.
Synthesis
The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are hereby incorporated in their entirety herein by reference.
The following abbreviations are used herein:
______________________________________                                    
Alata.       3-aminopropionic acid                                        
Boc          tert-butyloxycarbonyl                                        
Boc.sub.2 O  di-tert-butyl dicarbonate                                    
BOP          benzotriazolyl-N-oxytris(dimethylamino)-                     
             phosphonium hexafluorophosphate                              
BSTFA        N,O-bis(trimethylsilyl)triflouoromethyl-                     
             acetamide                                                    
Cbz          benzyloxycarbonyl                                            
DCC          1,3-dicyclohexylcarbodiimide                                 
DEAD         diethyl azodicarboxylate                                     
DEC          1-(3-dimethylaminopropyl)-3-                                 
             ethylcarbodiimide hydrochloride                              
DIEA         diisopropylethylamine                                        
DCHA         dicyclohexylamine                                            
DCM          dichloromethane                                              
DMAP         4-dimethylaminopyridine                                      
DMF          N,N-dimethyl formamide                                       
EtOAc        ethyl acetate                                                
EtOH         ethyl alcohol                                                
HOBt         1-hydroxybenzotriazole                                       
IBCF         iso-butyl chloroformate                                      
LAH          lithium aluminum hydride                                     
NCS          N-chlorosuccinimide                                          
NMM          N-methylmorpholine                                           
PPh.sub.3    triphenylphosphine                                           
pyr          pyridine                                                     
TBTU         2-(1H-Benzotriazol-1-yl)-1,1,3,3-                            
             tetramethyluronium tetrafluoroborate                         
TFA          trifluoroacetic acid                                         
THF          tetrahydrofuran                                              
______________________________________
A convenient method for the synthesis of the compounds of this invention utilizes a dipolar cycloaddition of nitrile oxides with appropriate dipolarophiles to prepare the isoxazoline rings present in compounds of Formula I (for reviews of 1,3-dipolar cycloaddition chemistry, see 1,3-Dipolar Cycloaddition Chemistry (Padwa, ed.), Wiley, New York, 1984; Kanemasa and Tsuge, Heterocycles 1990, 30, 719).
Scheme I describes one synthetic sequence to the compounds of the second embodiment of this invention. An appropriately substituted hydroxylamine is treated with NCS in DMF according to the method of Liu, et al. (J. Org. Chem. 1980, 45, 3916). The resulting hydroximinoyl chloride is then dehydrohalogenated in situ using TEA to give a nitrile oxide, which undergoes a 1,3-dipolar cycloaddition to a suitably substituted alkene to afford the isoxazoline. Alternatively, the oxime may be oxidatively chlorinated, dehydrochlorinated and the resulting nitrile oxide trapped by a suitable alkene under phase transfer conditions according to the method of Lee (Synthesis 1982, 508). Hydrolysis of the ester using conventional methods known to one skilled in the art of organic synthesis gives the desired acids. Intermediates containing alkali-sensitive functionality, such as nitrile, may be deesterified with excellent chemoselectivity using sodium trimethylsilanolate according to the procedure of Laganis and Ehenard (Tetrahedron Lett. 1984, 25, 5831). Coupling of the resulting acids to an appropriately substituted α- or β-amino ester using standard coupling reagents, such as DCC/HOBt, affords a nitrile-amide. The nitrile is then converted to the amidine via the imidate or thioimidate under standard conditions followed by ester saponification (LiOH, THF/H2 O). ##STR47##
An example of a related method of preparation for compounds within the second embodiment of the present invention is illustrated in Scheme Ia. Conversion of 3-(4-cyanophenyl)isoxazolin-5-ylacetic acid to the corresponding amidine, followed by protection as the Boc-derivative and saponification provides 3-(4-Boc-amidinophenyl)isoxazolin-5-ylacetic acid which is coupled with P-amino acid esters as shown. Deprotection provides the desired isoxazolinylacetyl-β-aminoalaninyl esters. Saponification as described above gives the free acids. ##STR48##
A further example of the synthesis of compounds within the second embodiment is shown in Scheme Ib. Cycloaddition of commerically available 4-cyanostyrene and t-butyl-3-oxoproprionate oxime using the method -described by Gree et al. (Bioorganic and Med. Chem. Lett. 1994, 253) provides t-butyl [5-(4-cyanophenyl)isoxazolin-3-yl]acetate. Using the procedures described above, this intermediate is converted to compounds of formula I wherein the isoxazoline ring is in the reverse orientation with respect to the compounds prepared via Schemes I and Ia. ##STR49##
Additional isoxazolinyl acetates useful as starting materials for the preparation of compounds of Formula I, wherein V is -(phenyl)-Q- and Q is other than a single bond, can be prepared by cycloaddition of a suitably substituted chloro or bromooxime with an ester of vinyl acetic acid as shown in Scheme Ic using literature methods or modifications thereof. (D. P. Curran & J. Chao, J. Org. Chem. 1988, 53, 5369-71; J. N. Kim & E. K. Ryu, Heterocycles 1990, 31, 1693-97). ##STR50##
The compounds of the present invention where R2 or R3 is e.g. alkoxycarbonyl may be prepared by reacting the free amidines, amines or guanidines with an activated carbonyl derivative, such as an alkyl chloroformate. In compounds of the second embodiment, the conversion of the free amines, amidines and guanidines to such acyl-nitrogen groups may optionally be performed prior to coupling an isoxazoline acetic acid with e.g β-amino acids, as illustrated in Scheme Ia.
The compounds of the present invention wherein Y is an oxyalkoxy group, e.g. alkoxycarbonyloxyalkoxy, may be prepared by reacting a suitably protected carboxylic acid of Formula I with an alkoxycarbonyloxyalkyl chloride in the presence of an iodide source, such as tetrabutylammonium iodide or potassium iodide, and an acid scavenger, such as triethylamine or potassium carbonate, using procedures known to those skilled in the art.
The appropriately substituted racemic β-amino acids may be purchased commercially or, as is shown in Scheme II, Method 1, prepared from the appropriate aldehyde, malonic acid and ammonium acetate according to the procedure of Johnson and Livak (J. Am. Chem. Soc. 1936, 58, 299). Racemic β-substituted-β-amino esters may be prepared through the reaction of dialkylcuprates or alkyllithiums with 4-benzoyloxy-2-azetidinone followed by treatment with anhydrous acid in ethanol (Scheme I, Method 2) or by reductive amination of β-keto esters as is described in WO9316038. (Also see Rico et al., J. Org. Chem. 1993, 58, 7948-51.) Enantiomerically pure β-substituted-β-amino acids can be obtained through the optical resolution of the racemic mixture or can be prepared using numerous methods, including: Arndt-Eistert homologation of the corresponding α-amino acids as shown in Scheme II, Method 3 (see Meier, and Zeller, Angew. Chem. Int. Ed. Engl. 1975, 14, 32; Rodriguez, et al. Tetrahedron Lett. 1990, 31, 5153; Greenlee, J. Med. Chem. 1985, 28, 434 and references cited within); and through an enantioselective hydrogenation of a dehydroamino acid as is shown in Scheme II, Method 4 (see Asymmetric Synthesis, Vol. 5, (Morrison, ed.) Academic Press, New York, 1985). A comprehensive treatise on the preparation of β-amino acid derivatives may be found in patent application WO 9307867, the disclosure of which is hereby incorporated by reference. ##STR51##
The synthesis of N2 -substituted diaminopropionic acid derivatives can be carried out via Hoffman rearrangement of a wide variety of asparagine derivatives as described in Synthesis, 266-267, (1981).
The appropriately substituted pyrrolidine-, piperidine- and hexahydroazepineacetic acids may be prepared using a number of methods. The pyrrolidines are conveniently prepared using an Arndt-Eistert homologation of the corresponding proline as shown in Scheme III, Method 1 (see Meier, and Zeller, Angew. Chem. Int. Ed. Engl. 1975, 14, 32; Rodriguez, et al. Tetrahedron Lett. 1990, 31, 5153; Greenlee, J. Med. Chem. 1985, 28, 434 and references cited within). The piperidines can be prepared by reduction of the corresponding pyridine as shown in Scheme III, Method 2. The hexahydroazepines are prepared by reduction of the corresponding vinylogous amide using sodium cyanoborohydride as depicted in Scheme III, Method 3. ##STR52##
Many additional appropriately substituted heterocycles are available commercially or can be readily modified by procedures known by one skilled in the art. Appropriately substituted morpholines can be prepared from amino acids via the sequence of steps depicted in Scheme IIIa, method 1 (see Brown, et. al. J. Chem. Soc. Perkin Trans I 1987, 547; Bettoni, et. al. Tetrahedron 1980, 36, 409; Clarke, F. H. J. Org. Chem. 1962, 27, 3251 and references therein.) N-ethoxycarbonylmethyl-1,2-diazaheterocyles are prepared by condensation of suitably substituted dibromides with benzylhydrazine followed by Mitsunobu reaction with ethyl hydroxyacetate and deprotection as shown in Scheme IIIa, method 2 (see Kornet, et. al. J. Pharm. Sci. 1979, 68, 377.; Barcza, et. al. J. Org. Chem. 1976, 41, 1244 and references therein.) ##STR53##
A general synthetic protocol to the compounds of the first embodiment of this invention is depicted in Scheme IV. Coupling of a suitable Boc-protected amino alcohol to an appropriately substituted phenol under Mitsunobu conditions (see Mitsunobu, Synthesis 1981, 1) is followed by oximation using hydroxylamine hydrochloride in 1:1 ethanol/pyridine. Isoxazoline formation, ester saponification and Boc-deprotection (33% TFA/DCM) then affords the compounds of this invention in good overall yield. ##STR54##
The synthesis of the spiro-fused isoxazolinyl imides of the third embodiment of the present invention is exemplified by the general protocol depicted in Scheme V. Dipolar cycloaddition of an oximinoyl chloride with a α-methylene diester affords an isoxazolinyl diester, which is deesterified using the silanolate method. Dehydration to the anhydride according to Ishihara, et al. (Chem. Pharm. Bull. 1992, 40, 1177-85) followed by imide formation using an appropriately substituted amino ester affords the spirocycle. Alternatively, the imide may be prepared directly from the isoxazoline diester according to Culbertson, et al. (J. Med. Chem. 1990, 33, 2270-75). Amidine formation or Boc deprotection followed by ester saponification then affords the compounds of this invention in good overall yield. ##STR55##
The synthesis of the spiro-fused isoxazolinyl amides of the third embodiment of the present invention is exemplified by the general protocol depicted in Scheme VI. Dipolar cycloaddition of an oximinoyl chloride with a α-methylene lactone affords the isoxazolinyl lactone, which is reacted with an appropriate amino ester to afford the amide (see The Chemistry of the Amides (Zabicky, ed.), p 96, Interscience, New York, 1970; Prelog, et al., Helv. Chim. Acta 1959, 42, 1301; Inubushi, et al., J. Chem. Soc., Chem. Commun. 1972, 1252). Amidine formation or Boc deprotection followed by ester saponification then affords the compounds of this invention in good overall yield. ##STR56##
The synthesis of the spiro-fused isoxazolinyl cycloalkenes of the third embodiment of the present invention is exemplified by the general protocol depicted in Scheme VII. Dipolar cycloaddition of an oximinoyl chloride with an appropriately substituted α-methylene lactone affords the isoxazolinyl lactone. The lactone is then reacted with an appropriate lithium dimethyl alkylphosphonate, followed by PCC oxidation. The resulting diketophosphonate undergoes an intramolecular Wittig reaction in the presence of K2 CO3 /18-crown-6 according to the method described by Lim and Marquez (Tetrahedron Lett. 1983, 21, 5559). Amidine formation or Boc deprotection followed by ester saponification then affords the compounds of this invention in good overall yield. ##STR57##
The dipolarophiles used to prepare the compounds of this invention may be prepared by numerous methods. The ω-alkenoic ester class of dipolarophile may be purchased commercially or prepared by oxidation of the corresponding ω-alkenols by the method of Corey and Schmidt (Tetrahedron Lett. 1979, 399, Scheme VIII, Method 1). The α-methylene diester and α-methylene lactone class of dipolarophile may be purchased commercially or can be prepared by numerous methods from the corresponding diester (see Osbond, J. Chem. Soc. 1951, 3464; Ames and Davey, J. Chem,. Soc 1958, 1794; Vig, et al., Ind. J. Chem. 1968, 6, 60; Grieco and Hiroi, J. Chem, Soc., Chem, Commun. 1972, 1317, Scheme VIII, Method 2). The 3-(styryl)propionic ester class of dipolarophile may be prepared by palladium-catalyzed cross coupling of the appropriately substituted bromo- or iodohydrocinnamic acid to a vinylmetal species according to methods cited within Mitchell (Synthesis 1992, 803) and Stille (Angew. Chem. Int. Ed. Engl. 1986, 25, 508, Scheme VIII, Method 3). ##STR58##
Compounds of Formula I wherein b is a double bond can be prepared using one of the routes depicted in Scheme IX. Bromination followed by subsequent dehydrobromination of a suitably substituted methyl 3-(cyanophenyl)isoxazolin-5-ylacetate, prepared as described above, using the method of Elkasaby & Salem (Indian J. Chem. 1980, 19B, 571-575) provides the corresponding isoxazole intermediate. Alternately, this intermediate can be obtained by 1,3-dipolar cycloaddition of a cyanophenylnitrile oxide (prepared from the corresponding chlorooxime as described in Scheme I) with an appropriate alkyne to give the isoxazole directly. Hydrolysis of the ester using conventional methods known to one skilled in the art of organic synthesis gives the acetic acids. Coupling of the resulting acids to an appropriately substituted α- or β-amino ester using standard coupling reagents, such as TBTU, affords a nitrile-amide. The nitrile is then converted to the amidine via the imidate or thioimidate under standard conditions to give the prodrug esters. Saponification gives the acids. ##STR59##
Compounds of Formula I wherein R1 is (R2) (R3)N(R2 N═)CN(R2)-- and V is phenylene are prepared as illustrated in Scheme X. Cycloaddition of an appropriately N-protected aminophenylaldoxime with vinyl acetic acid, t-butyl ester, using the conditions described above provides t-butyl [3-(4-t-butyloxycarbonylaminophenyl)isoxazolin-5-yl]acetate. Hydrolysis of the ester with lithium hydroxide provides the free acid which can be coupled with a suitably substituted methyl 3-aminopropionate as previously described. After deprotection, the aniline is converted to the corresponding guanidine using the method described by Kim et al. (Tetrahedron Lett. 1993, 48, 7677). A final deprotection step to remove the BOC groups provides guanidino compounds of Formula I. ##STR60##
An example of the preparation of compounds of the second embodiment wherein R1 -U is a benzamide is illustrated in Scheme XI. Conversion of the 3-(4-cyanophenyl)isoxazolin-5-yl-β-aminoalaninyl esters to the amides can be accomplished by reaction of the nitrile with an appropriate alcohol under acidic conditions. (J. Med. Chem. 1991, 34, 851.) The substituted amides can be accessed by allowing the 3-(4-cyanophenyl)isoxazolin-5-yl-β-aminoalaninyl esters to react with an appropriate halogenated compound (Synthesis, 1978, 303. Saponification as described above gives the free acids. ##STR61##
The compounds of the invention where U is a pyridyl may be prepared by several methods. 2-Amino-4-pyridyl analogs can be easily accessed from readily available 2-bromo-4-pyridylcarboxaldehyde (Corey, E. J. et. al. Tetrahedron Lett. 1983, 32, 3291). The desired amino compound can be suitably introduced by displacement of the bromo substituent with a suitable ammonia source or alternatively with sodium azide followed by reduction via standard techniques known to those in the art. 2-Amidino-5-pyridyl analogs can be accessed from 2-bromo-5-pyridylcarboxaldehyde by displacement of the bromide at an appropriate stage in the synthesis with KCN. Conversion of the nitrile to the requisite amidine then affords the desired products. 6-Amino-3-pyridyl analogs can be easily accessed (according to the method described for the preparation of 2-amino-5-pyridyl analogs) from 6-chloro-3-pyridylcarboxaldehyde. This was obtained in part from 6-chloro-3-pyridylcarboxylic acid (Aldrich) via techinques known in the art. 6-Amidino-3-pyridyl analogs can be readily accessed from 6-chloro-3-pyridylcarboxaldehyde via techniques described for 2-amidino-5-pyridylanalogs.
The preparation of quinuclidine carboxaldehyde starting materials may be done as follows. 4-Cyanoquinuclidine prepared by the method of Kanai, T. et al, (Het., 1992, 34, 2137), can be converted to quinuclidine-4-carboxaldehyde by standard conditions and homologated by the method of (Tetrahedron Lett. 1987, 28, 1847) to the desired aldehyde. Conversion of the aldehyde to the oxime followed by chlorination to the chlorooxime should then afford the key quinuclidine chlorooxime which can then be further elaborated to the desired compounds.
The synthesis of spiro-fused isoxazolinyl amines of the third embodiment of the present invention is exemplified by the general protocol depicted in Scheme XII. Dipolar cycloaddition of a suitable oxime with a suitably protected methylenecycloamine, prepared by methods known in the literature (De Amici, M.; Frolund, B.; Hjeds, H.; Krogsgaard-Larson, P. Eur. J. Med. Chem. 1991, 26, 625; Mimura, M., et. al. Chem. Pharm. Bull. 1993, 41, 1971; Labouta, I. M.; Jacobsen, P.; Thorbek, P.; Krogsgaard-Larson, P.; Hjeds, H. Acta Chem. Scand., Ser. B 1982, 36, 669), yields the spirocyclic amine after deprotection. This amine can be functionalized with a serine beta-lactone (Arnold, L. D.; Kalantar, T. H.; Vederas, J. C. J. Am. Chem. Soc. 1985, 107, 7105) providing an optically active product. Alternatively, the amine can be reacted with a 3-iodo or 3-chloroalanine derivative (I: Marki, W.; Schwyzer, R. Helv. Chim. Acta 1975, 58, 1471; Cl: Bigge, C. F.; Wu J.-P.; Druumond, J. R. Tetrahedron Lett. 1991, 32, 7659; Benoiton, L. Can. J. Chem. 1968, 46, 1549) to give a racemic product. ##STR62## The cycloaddition can also be performed after the introduction of the propionyl side chain as shown in Scheme XIII. ##STR63##
The compounds of Tables 12 and 13 were made using combinatorial synthetic methodology as shown in Scheme XIV. Thus, a resin was derivatized and to it was coupled the protected 2,3-diaminoproprionate. Following deprotection of N3, the desired isoxazoline carboxylic acid was coupled to N3. The final product was removed from once the terminal amine of the isoxazoline carboxylic acid was converted to its desired form. ##STR64##
The compounds of this invention and their preparation can be further understood by the following procedures and examples, which exemplify but do not constitute a limit of their invention.
EXAMPLE 1 3- (4-[2-Piperidin-4-yl)ethoxy]-phenyl]-(5R,S)-isoxazolin-5-ylacetic Acid, Trifluoroacetic Acid Salt
Part A. Preparation of 2-(4-N-t-Butyloxycarbonylpiperidinyl)ethanol
This material was prepared from 4-piperidine-2-ethanol according to European Patent Application Publication Number 478363 A2.
Part B. 4-[2-(N-t-Butyloxycarbonylpiperidinyl-4-yl)ethoxy]benzaldehyde
To a solution of 2-(4-N-t-Butyloxycarbonylpiperidinyl)ethanol (7.71 g, 33.6 mmol), 4-hydroxybenzaldehyde (4.11 g, 33.6 mmol) and PPh3 (8.82 g, 33.6 mmol) in THF (60 mL) at -20° C. was added a solution of DEAD (5.3 mL, 33.7 mmol) in THF (30 mL) over 2 hours. During the addition, a deep red solution resulted, which changed to a golden color upon warming to room temperature overnight (18 hours). At this time the solution was concentrated and redissolved in EtOAc. It was then washed with water, 0.1M HCl, 1M NaOH, sat. NaCl and dried (MgSO4). Concentration gave a solid (˜20 g), which was purified using flash chromatography (10-20-30-40-50% EtOAc/hexanes step gradient), affording 7.82 g (70%) of the desired ether after pumping to constant weight; mp 76.4-79.7° C.; 1 H NMR (300 MHz, CDCl3) δ 9.88 (s 1H), 7.83 (d, J=8.4 Hz, 2H), 6.98 (d, J=8.4 Hz, 2H), 4.10 (bd, J=12.8 Hz, 2H), 4.04 (t, J=6.6 Hz 2H), 2.69 (bt, 2H), 1.84 (m, 2H), 1.70 (bd J=14.3 Hz, 2H), 1.46 (s, 9H, overlapped with m, 2H), 1.10 (m, 2H).
Part C. 4-[2-(N-t-Butyloxycarbonylpiperidin-4-yl)ethoxy]benzaldoxime
To a solution of 4-[2-(N-t-butyloxycarbonylpiperidin-4-yl)ethoxy]benzaldehyde (3.16 g, 9.48 mmol) in MeOH (20 mL) was added hydroxylamine hydrochloride (1.27 g, 18.3 mmol) and 2M NaOH (7 mL, 14 mmol). The resulting suspension was stirred overnight at room temperature (18 hours). The mixture was brought to pH 4 using 1M HCl, followed by filtration and water wash. The crystals were dried under vacuum over P2 O5, affording 2.88 g (87%); mp: 114.4-116.1° C.; 1 H NMR (300 MHz, CDCl3) δ 8.09 (s, 2H), 7.51 (d, J=8.8 Hz, 2H), 6.89 (d, J=8.8 Hz, 2H), 4.10 (b, 2H), 4.03 (t, J=6.2 Hz 2H), 2.71 (bt, 2H), 1.73 (m, 4H), 1.46 (s, 9H), 1.19 (m, 2H).
Part D. 4-[2-(N-t-Butyloxycarbonylpiperidin-4-yl)ethoxy]benzaldoximinoyl Chloride
To a solution of 4-[2-(N-t-butyloxycarbonylpiperidin-4-yl)ethoxy]benzaldoxime (955 mg, 2.74 mmol) in DMF (5 mL) was added NCS (366 mg, 2.74 mmol) in 3 portions. After 3 hours, the solution was diluted with EtOAc and washed with water, sat. NaCl, dried (MgSO4) and concentrated. The resulting solid was crystallized from ether/hexanes to give 548 mg (52%) of the oximinoyl chloride; mp. 119.3-119.9° C.; 1 H NMR (300 MHz, CDCl3) δ 8.37 (bs 1H), 7.77 (d, J=8.8 Hz, 2H), 6.88 (d, J=8.8 Hz, 2H), 4.12 (bd, J=13.2 Hz, 2H), 4.04 (t, J=6.2 Hz 2H), 2.72 (bt, J=12.1 Hz, 2H), 1.70 (m, 5H), 1.46 (s, 9H), 1.10 (m, 2H).
Part E. Methyl 3-[4-{2-(N-t-Butyloxycarbonylpiperidin-4-yl)ethoxy}phenyl]-(5R, S)-isoxazolin-5-ylacetate
To a solution of 4-[2-(N-t-butyloxycarbonylpiperidin-4-yl)ethoxy]benzaldoximinoyl chloride (400 mg, 1.045 mmol) and methyl 3-butenoate (200 mg, 2.00 mmol) was added TEA (0.15 mL, 1.1 mmol). The resulting suspension was heated at reflux for 5 hours, cooled to room temperature and diluted with EtOAc. It was then washed with 0.1M HCl, water, sat. NaCl, dried (MgSO4) and concentrated. The resulting solid was crystallized from DCM/hexanes to give 357 mg (77%) of the isoxazoline; mp: 139.1-140.9° C.; 1 H NMR (300 MHz, CDCl3) δ 7.59 (d, J=8.8 Hz, 2H), 6.90 (d, J=8.8 Hz, 2H), 5.08 (m, 1H), 4.10 (bd, J=13.2 Hz, 2H), 4.04 (t, J=5.9 Hz 2H), 3.73 (s, 3H), 3.53 (dd, J=16.5, 10.1 Hz, 1H), 3.10 (dd, J=16.8, 7.1 Hz, 1H), 2.88 (dd, J=16.1, 5.9 Hz, 1H), 2.71 (bt, J=12.8 Hz, 2H), 2.64 (dd, J=15.8, 7.7 Hz, 1H), 1.72 (m, 5H), 1.46 (s, 9H), 1.08 (m, 2H).
Part F. 3-[4-{2-(N-t-Butyloxycarbonylpiperidin-4-yl)ethoxy}phenyl]-(5R,S)-isoxazolin-5-ylacetic Acid
To a solution of methyl 3-[4-{2-(N-t-butyloxycarbonylpiperidin-4-yl)ethoxy}phenyl]-(5R,S)-isoxazolin-5-ylacetate (47 mg, 0.105 mmol) in THF (2 mL) was added 0.5M LiOH (1 mL, 0.5 mmol). The reaction was stirred at room temperature for 5 hours, then was acidified to pH 3 using 0.1M HCl. The mixture was washed with DCM and the combined organic fraction dried (MgSO4) and concentrated. The resulting solid was crystallized from EtOAc/hexanes to give 34 mg (74%) of the carboxylic acid; mp: 169.1-170.6° C.; 1 H NMR (300 MHz, CDCl3) δ 7.60 (d, J=8.8 Hz, 2H), 6.91 (d, J=8.8 Hz, 2H), 5.10 (m, 1H), 4.08 (bd, 2H, overlapped with t, J=5.9 Hz 2H), 3.55 (dd, J=16.5, 10.2 Hz, 1H), 3.11 (dd, J=16.8, 7.0 Hz, 1H), 2.93 (dd, J=16.1, 6.2 Hz, 1H), 2.71 (m, 3H), 2.00 (m, 2H), 1.72 (m, 5H), 1.46 (s, 9H).
Part G. 3-(4-[2-(Piperidin-4-yl)ethoxylphenyl]-(5R,S)-isoxazolin-5-ylacetic Acid, Trifluoroacetic Acid Salt
To a solution of 3-[4-{2-(N-t-Butyloxycarbonylpiperidin-4-yl)ethoxy}phenyl]-(5R,S)-isoxazolin-5-ylacetic acid (53 mg, 0.12 nmol) in DCM (2 mL) was added TFA (1 mL, 13 mmol). After 1.5 hours, the product was crystallized by the addition of ether, affording 33 mg (60%) of the amino acid; mp: 142.4-143.1° C.; 1 H NMR (300 MHz, CDCl3) δ 7.59 (dd, J=8.8, 2.6 Hz, 2H), 6.96 (dd, J=8.8, 2.6 Hz, 2H), 5.03 (m, 1H), 4.10 (m, 2H), 3.55 (ddd, J=16.8, 10.3, 2.2.Hz, 1H), 3.38 (bd, J=12.4 Hz, 2H), 3.16 (ddd, J=17.2, 7.7, 2.2 Hz, 1H), 2.98 (bt, J=13.2 Hz, 2H), 2.69 (m, 2H), 2.01 (bd, J=14.3 Hz, 2H), 1.91 (m, 1H), 1.80 (m, 2H), 1.46 (m, 2H).
EXAMPLE 4 2-[3-(4-[2-(Piperidin-4-yl)ethoxy]phenyl)isox-azolin-5-yl]-2-(S)-(benzyloxycarbonylamino)acetate, Trifluoroacetic Acid Salt
Part A. Benzyl 2-(S)-[[(benzyloxy)carbonyl]amino]-3-butenoate
This material was prepared from N-Cbz-l-glutamic acid α-benzyl ester according to Krol, et al. (J. Org. Chem, 1991, 728).
Part B. Benzyl (2S)-(5R,S)-[3-[4-{(2-N-t-Butyloxycarbonylpiperidin-4-yl)ethoxy}phenyl]isoxazolin-5-yl{[(benzyloxy)carbonyl]amino}]acetate
To a solution of 4-[(2-N-t-butyloxycarbonylpiperidin-4-yl)ethoxy]benzaldoxime (852 mg, 2.44 mmol) and benzyl l-2-[[(benzyloxy)carbonyl]amino]-3-butenoate (612 mg, 1.88 mmol) in DCM (10 mL) was added 5% NaOCl (common household bleach, 4 mL, 2.8 mmol). The mixture was rapidly stirred at room temperature for 22 hours, after which time it was diluted with water and DCM. After separation of the layers, the aqueous was washed with DCM (3x). The combined organic extracts were dried (MgSO4) and concentrated in vacuo, giving 1.4 g. Purification using flash chromatography (10% EtOAc/hexanes--30% EtOAc/hexanes) then afforded 886 mg (70%) of an oily product as a 2.5:1 mixture of the erythro and threo isomers; 1 H NMR (400 MHz, CDCl3) δ 7.50 (m, 2H), 7.34 (m, 5H), 7.23 (m, 5H), 6.87 (d, J=8.8 Hz, 2H), 5.47 (bd, 1H), 5.12 (m, 5H), 4.60 (m, 1H), 4.07 (m, overlapped with 4.03 (t, J=6.1 Hz, 4H) , 3.36 (m, 2H), 2.71 (bt, J=12.7 Hz, 2H), 1.70 (m, 5H), 1.45 (s, 9H), 1.18 (m, 2H); Anal. Calc. for C38 H45 N3 O8 : C, 67.93; H, 6.76; N, 6.26. Found: C, 67.95; H, 6.77; N, 6.17.
Part C. (2S)-(5R,S)-[3-[4-{(2-N-t-Butyloxycarbonylpiperidin-4-yl)ethoxy}phenyl]isoxazolin-5-yl{[(benzyloxy)carbonyl]amino}]acetic Acid
A solution of benzyl (2S)-(5R,S)-[3-[4-{(2-N-t-butyloxycarbonylpiperidin-4-yl)ethoxy}phenyl]isoxazolin-5-yl{[(benzyl-oxy)carbonyl]amino}]acetate (875 mg, 1.302 mmol) in THF (5 mL) was saponified over 5 hours using 0.5M LiOH (3.5 mL) according to Example 1, Part F. To the crude product was added methanol, causing crystallization of one of the diastereomers. Filtration and pumping to constant weight gave 295 mg (39%); mp: 216.1° C.; 1 H NMR (400 MHz, DMSO-d6, 80° C.) δ 7.50 (d, J=8.9 Hz, 2H), 7.23 (s, 5H), 6.96 (d, J=8.9 Hz, 2H), 6.17 (bs, 1H), 4.99 (m, 3H), 4.07 (t, J=6.1 Hz, 2H), 3.90 (m, 3H), 3.35 (d, J=9.3 Hz, 2H), 2.72 (bt, J=12.4 Hz, 2H), 1.67 (m, 5H), 1.39 (s, 9H), 1.08 (m, 2H). The filtrate was concentrated in vacuo and pumped until constant weight was achieved, giving 200 mg (26%) of the carboxylic acids as a mixture of erythro- and threo-isomers; TLC (silica gel 60, 20% MeOH/CHCl3) Rf =0.23, Mass Spectrum (ESI, e/z, relative abundance) 582 (M+H)+, 32%; 526 (M-C4 H9 +H2)+, 100%; 482 (M-Boc+H2)+, 91%).
Part D. (2S)-(5R,S)-[3-[4-{(2-Piperidin-4-yl)ethoxyl}phenyl]isoxazolin-5-yl{[(benzyloxy)carbonyl]amino}]acetic Acid (isomer A)
(2S)-(5R,S)-[3-[4-{(2-N-t-Butyloxycarbonylpiperidin-4-yl)ethoxy}phenyl]isoxazolin-5-yl{[(benzyloxy)carbonyl]amino}]acetic acid (23 mg, 0.039 mmol) was Boc-deprotected using 33% TFA/DCM according to Example 1, Part G, giving 15 mg (79%); mp: 302° C. (dec); 1 H NMR (400 MHz, DMSO-d6, 60° C.) δ 7.57 (d, J=8.8 Hz, 2H), 7.30 (s, 5H), 6.99 (d, J=8.8 Hz, 2H), 5.05 (s, 2H, coincident with m, 1H), 4.35 (d, J=4.9 Hz,, 1H), 4.09 (t, J=6.1 Hz, 2H), 3.52 (dd, J=17.3, 10.7 Hz, 1H), 3.26 (m, 3H), 2.88 (dt, J=12.7, 2.7 Hz, 2H), 1.88 (bd, J=14.4 Hz, 2H), 1.80 (m, 1H), 1.72 (m, 2H), 1.38 (m, 2H).
Part D'. (2S)-(5R,S)-[3-[4-{(2-Piperidin-4-yl)ethoxy}phenyl]isoxazolin-5-yl{[(benzyloxy)carbonyl]amino}]acetic Acid, Trifluoroacetic Acid Salt (isomer B)
(2S)-(5R,S)-[3-[4-{(2-N-t-Butyloxycarbonylpiperidin-4-yl)ethoxy}phenyl]isoxazolin-5-yl{[(benzyloxy)carbonyl]amino}]acetic acid (177 mg, 0.304 nmol) was Boc-deprotected using 33% TFA/DCM according to Example 1, Part G, giving 3 mg (2%) of the TFA salt; mp: >400° C.; 1 H NMR (400 MHz, DMSO-d6, 60° C.) δ 8.48 (bs,0.5H) , 8.15 (bs, 0.5H), 7.55 (d, J=8.9 Hz, 2H), 7.30 (m, 5H), 6.97 (d, J=8.9 Hz, 2H), 5.05 (s, 2H), 4.96 (m, 1H), 4.33 (m, 1H) , 4.07 (t, J=6.3 Hz, 2H) , 3.38 (m, 2H) , 3.26 (bd, J=12.0 Hz, 2H), 2.87 (m, 2H), 1.86 (bd, J=14.2 Hz, 2H), 1.78 (m, 1H), 1.70 (apparent q, J=6.3 Hz, 2H), 1.36 (bq, J=13.2 Hz, 2H).
EXAMPLE 6 3-(3-[4- (Piperidin-4-ylmethoxy)phenyl]-(5R,S)-isoxazolin-5-yl)propionic Acid, Trifluoroacetic Acid Salt
Part A. Ethyl N-t-Butyloxycarbonylpiperidine-4-carboxylate
To a stirred solution of ethyl isonipecotate (20.01 g, 0.1273 mol) in EtOAc (100 mL) at 0° C. was added dropwise a solution of Boc2 O (27.76 g, 0.1272 mol) in EtOAc (50 mL). The mixture was allowed to warm to room temperature overnight. After 20 hours, the mixture was washed with water, 0.1M HCl, sat. NaHCO3, sat. NaCl and dried (MgSO4). Concentration and pumping under vacuum to constant weight gave 32.54 g (99%) of the desired carbamate as a mobile oil; 1 H NMR (300 MHz, CDCl3) δ 4.13 (q, J=7.0 Hz, 2H), 4.03 (dm, J=13.6 Hz 2H), 2.81 (m, 2H), 2.41 (m, 1H), 1.86 (dm, J=13.6 Hz, 2H), 1.62 (m, 2H), 1.44 (s, 9H), 1.24 (t, J=7.0 Hz, 3H).
Part B. N-t-Butyloxycarbonylpiperidin-4-ylmethanol
To a solution of ethyl N-t-butyloxycarbonylpiperidine-4-carboxylate (32.34 g, 0.1257 mol) in THF (100 mL) at 0° C. was added dropwise 1M LAH in THF (87.9 mL, 0.0879 mol). After 2 hours, excess hydride was quenched by the addition of water (3.2 mL), 2M NaOH (3.2 mL) and water (10 mL). The mixture was filtered, washed with EtOAc and the filtrate washed with water, sat. NaCl, dried (MgSO4) and concentrated. Pumping to constant weight gave 22.72 g (84%); mp: 79.2-81.1° C.; 1 H NMR (300 MHz, CDCl3) δ 4.12 (bd, J=12.8 Hz 2H), 3.49 (d, J=6.2 Hz, 2H), 2.68 (dt, J=13.2, 1.8 Hz, 2H), 1.69 (m, 3H), 1.44 (s, 9H, overlapped with m, 1H), 1.14 (m, 2H).
Part C. 4-(N-t-Butyloxycarbonylpiperidin-4-ylmethoxy)-benzaldehyde
To N-t-butyloxycarbonylpiperidin-4-ylmethanol (7.87 g, 36.5 mmol), p-hydroxybenzaldehyde (4.46 g, 36.5 mmol) and PPh3 (9.59 g, 36.5 mmol) in THF (100 mL) at -20° C. was added DEAD (5.75 mL, 36.5 mmol) in THF (50 mL) according to Example 1, Part B, affording 8.14 g (70%); mp: 115.6-116.8° C.; 1 H NMR (300 MHz, CDCl3) δ 9.86 (s, 1H), 7.81 (d, J=8.8 Hz, 2H), 6.96 (d, J=8.8 Hz, 2H), 4.15 (bd, J=13.2 Hz 2H), 3.87 (d, J=6.6 Hz, 2H), 2.74 (dt, J=12.4, 1.8 Hz, 2H), 1.97 (m, 1H), 1.81 (bd, J=12.8 Hz, 2H), 1.45 (s, 9H), 1.27 (dq, J=12.1, 4.0 Hz, 2H).
Part D. 4-(N-t-Butyloxycarbonylpiperidin-4-ylmethoxy)-benzaldoxime
A mixture of 4-(N-t-butyloxycarbonylpiperidin-4-ylmethoxy)benzaldehyde (3.16 g, 9.89 mmol) and hydroxylamine hydrochloride (1.27 g, 18.3 mmol) in 9:1 MeOH/pyridine (30 mL) was heated at reflux for 18 hours. The mixture was cooled to room temperature and concentrated to dryness. The residue was dissolved in EtOAc and washed with 0.1M HCl (3x), water, sat. CuSO4 (2x), water, sat. NaCl, dried (MgSO4) and concentrated, giving 3.19 g (96%) of the oxime; mp: 140.1-141.8° C.; 1 H NMR (300 MHz, CDCl3) δ 8.07 (s, 1H), 7.48 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 4.14 (bs, 2H), 3.80 (d, J=6.2 Hz, 2H), 2.71 (bt, J=12.4 Hz, 2H), 1.95 (m, 1H), 1.80 (bd, J=12.4 Hz, 2H), 1.45 (s, 9H), 1.26 (m, 2H).
Part E. 4-(N-t-Butyloxycarbonylpiperidin-4-ylmethoxy)-benzaldoximinoyl Chloride
4-(N-t-Butyloxycarbonylpiperidin-4-ylmethoxy)-benzaldoxime (3.19 g, 9.54 mmol) in DMF (10 mL) was reacted with NCS (1.27 g, 9.51 mmol) for 18 hours according to Example 1, Part D to afford the hydroximinoyl chloride (1.17 g, 33%); mp: 178.0-179.8° C.; 1 H NMR (300 MHz, CDCl3) δ 7.75 (d, J=9.0 Hz, 2H), 6.86 (d, J=9.0 Hz, 2H), 4.17 (bd, J=12.4 Hz, 2H), 3.80 (d, J=6.2 Hz, 2H), 2.74 (dt, J=12.8, 1.8 Hz, 2H), 1.95 (m, 1H), 1.81 (bd, J=12.1 Hz, 2H), 1.46 (s, 9H), 1.27 (dq, J=12.5, 4.0 Hz, 2H).
Part F. Methyl 3-(3-[4-(N-t-Butyloxycarbonylpiperidin-4-ylmethoxy)phenyl]-(5R,S)-isoxazolin-5-yl)propionate
4-(N-t-Butyloxycarbonylpiperidin-4-ylmethoxy)benzaldoximinoyl chloride (738 mg, 2.00 mmol), methyl 4-pentenoate (230 mg, 2.02 mmol) and TEA (0.28 mL, 2.0 mmol) were heated at reflux for 1 hour according to Example 1, Part E. Crystallization from ether/hexanes afforded 537 mg (60%). mp: 97.9-99.9° C.; 1 H NMR (300 MHz, CDCl3) δ 7.57 (d, J=9.0 Hz, 2H), 6.87 (d, J=9.0 Hz,2H), 4.74 (m, 1H), 4.15 (bd, J=13.2 Hz, 2H), 3.81 (d, J=6.2 Hz, 2H), 3.67 (s, 3H), 3.40 (dd, J=16.5, 10.2 Hz, 1H), 2.95 (dd, J=16.5, 7.3 Hz, 1H), 2.73 (dt, J=13.2, 1.1 Hz, 2H), 2.52 (t, J=7.3 Hz, 2H), 1.98 (q, J=7.0 Hz, 2H, overlapping m, 1H), 1.81 (bd, J=12.8 Hz, 2H), 1.45 (s, 9H), 1.26 (dq, J=12.4, 3.7 Hz, 2H).
Part G. 3-(3-[4-(N-t-Butyloxycarbonylpiperidin-4-ylmethoxy)phenyl]-(5R,S)-isoxazolin-5-yl)propionic Acid
Methyl 3-(3-[4-(N-t-butyloxycarbonylpiperidin-4-ylmethoxy)phenyl]-(5R,S)-isoxazolin-5-yl)propionate (250 mg, 0.560 mmol) was saponified using 0.5M LiOH (2 mL, 1 mmol) in THF (2 mL). The reaction was stirred at room temperature for 3 hours, according to Example 1, Part F. The resulting solid was crystallized from DCM/hexanes to give 163 mg (67%) of the carboxylic acid; mp: 146.5-147.7° C.; 1 H NMR (300 MHz, CDCl3) δ 7.57 (d, J=8.8 Hz, 2H), 6.88 (d, J=8.8 Hz, 2H), 4.75 (m, 1H), 3.81 (d, J=6.2 Hz, 2H), 3.41 (dd, J=16.5, 10.3 Hz, 1H), 2.95 (dd, J=16.5, 7.3 Hz, 1H), 2.75 (bt, J=12.4 Hz, 2H), 2.57 (t, J=7.3 Hz, 2H), 1.97 (m, 3H), 1.81 (bd, J=12.1 Hz, 2H), 1.45 (s, 9H), 1.24 (m, 2H).
Part H. 3-(3-[4-(Piperidin-4-ylmethoxy)phenyl]-(5R,S)-isoxazolin-5-yl)propionic Acid, Trifluoroacetic Acid Salt
3-(3-[4-(N-t-Butyloxycarbonylpiperidin-4-ylmethoxy)phenyl]-(5R,S)-isoxazolin-5-yl)propionic acid (103 mg, 0.238 mmol) was Boc-deprotected using 33% TFA/DCM according to Example 1, Part G, giving 88 mg (83%) of the TFA salt; mp: 179.1-181.8° C.; 1 H NMR (400 MHz, MeOH-d4) δ 7.60 (d, J=9.0 Hz, 2H) , 6.97 (d, J=9.0 Hz, 2H), 4.73 (m, 1H), 3.94 (d, J=6.1 Hz, 2H), 3.46 (m, 3H), 3.06 (m, 3H), 2.45 (dt, J=7.3, 1.2 Hz, 2H), 2.16 (m, 1H), 2.08 (bd, J=15.4 Hz, 2H), 1.94 (q, J=6.6 Hz, 1H), 1.64 (dq, J=14.2, 4.2 Hz, 2H).
EXAMPLE 7 3-[4-(Piperidin-4-ylmethoxy)phenyl]-(5R,S)-isoxazolin-5-ylacetic Acid, Trifluoroacetic Acid Salt
Part A. Methyl 3-[4-(N-t-Butyloxycarbonylpiperidin-4-ylmethoxy)phenyl]-(5R,S)-isoxazolin-5-ylacetate
4-(N-t-Butyloxycarbonylpiperidin-4-ylmethoxy)benzaldoximinoyl chloride (412 mg, 1.12 mmol), methyl 3-butenoate (200 mg, 2.00 mmol) and TEA (0.18 mL, 1.3 mmol) were heated at reflux for 2 hours according to Example 1, Part E. Crystallization from chloroform/cyclohexane afforded 329 mg (68%). mp: 97.9-99.9° C.; 1 H NMR (300 MHz, CDCl3) δ 7.58 (d, J=8.8 Hz, 2H), 6.88 (d, J=8.8 Hz,2H), 5.04 (m, 1H), 4.15 (bd, J=13.2 Hz, 2H), 3.81 (d, J=6.2 Hz, 2H), 3.71 (s, 3H), 3.54 (dd, J=16.8, 10.3 Hz, 1H), 3.08 (dd, J=16.8, 7.3 Hz, 1H), 2.86 (dd, J=16.1, 5.9 Hz, 1H), 2.73 (dt, J=12.8, 1.8 Hz, 2H), 2.62 (dd, J=15.8, 7.7 Hz, 1H), 1.95 (m, 1H), 1.81 (bd, J=13.2 Hz, 2H), 1.45 (s, 9H), 1.25 (dq, J=12.8, 4.4 Hz, 2H).
Part B. 3-[4-(N-t-Butyloxycarbonylpiperidin-4-ylmethoxy)phenyl]-(5R,S)-isoxazolin-5-ylacetic Acid
Methyl 3-[4-(N-t-butyloxycarbonylpiperidin-4-ylmethoxy)phenyl]-(5R,S)-isoxazolin-5-ylacetate (329 mg, 0.762 mmol) was saponified using 0.5M LiOH (3 mL, 1.5 mmol) in THF (5 mL). The reaction was stirred at reflux for 4 hours, according to Example 1, Part F to give 72 mg (22%) of the carboxylic acid; mp: 164.0-164.8° C.; 1 H NMR (300 MHz, CDCl3) δ 7.58 (d, J=8.8 Hz, 2H) , 6.88 (d, J=8.8 Hz, 2H), 5.07 (m, 1H), 4.15 (bd, J=13.6 Hz, 2H), 3.82 (d, J=6.2 Hz, 2H), 3.53 (dd, J=16.8, 10.3 Hz, 1H), 3.10 (dd, J=16.8, 7.0 Hz, 1H), 2.91 (dd, J=16.1, 5.9 Hz, 1H), 2.73 (dt, J=14.6, 1.8 Hz, 2H), 2.68 (dd, J=16.1, 7.3 Hz, 1H), 1.97 (m, 1H), 1.81 (bd, J=13.2 Hz, 2H), 1.45 (s, 9H), 1.26 (dq, J=12.8, 4.4 Hz, 2H).
Part C. 3-[4-(Piperidin-4-ylmethoxy)phenyl]-(5R,S)-isoxazolin-5-ylacetic Acid, Trifluoroacetic Acid Salt
3-[4-(N-t-Butyloxycarbonylpiperidin-4-ylmethoxy)phenyl]-(5R,S)-isoxazolin-5-ylacetic acid (72 mg, 0.172 mmol) was Boc-deprotected using 33% TFA/DCM according to Example 1, Part G, giving 64 mg (94%) of the TFA salt; mp: 220° C. (dec); 1 H NMR (300 MHz, MeOH-d4) δ 7.61 (d, J=9.2 Hz, 2H), 6.97 (d, J=9.2 Hz, 2H), 5.04 (m, 1H), 3.95 (d, J=5.9 Hz, 2H), 3.56 (dd, J=17.2, 10.2 Hz, 1H), 3.45 (bd, J=12.8 Hz, 2H), 3.18 (dd, J=17.2, 7.3 Hz, 1H), 3.04 (dt, J=10.2, 2.9 Hz, 2H), 2.69 (m, 2H), 2.18 (m, 1H), 2.08 (bd, J=14.6 Hz, 2H) 1.63 (bq, 2H).
EXAMPLE 8 3-[4-(2-Piperidin-4-yl)ethoxyphenyl]-(5R,S)-isoxazolin-5-ylpropionic Acid, Trifluoroacetic Acid Salt
This material was prepared analogously to Example 1, giving the desired material; mp: 114.8-115.7° C.; 1 H NMR (300 MHz, CD3 OD) δ 7.59 (d, J=8.4 Hz, 2H), 6.95 (d, J=8.4 Hz, 2H), 4.72 (m, 1H), 4.07 (t, J=5.9 Hz, 2H), 3.47 (dd, J=16.8. 10.2 Hz, 1H), 3.37 (dd, J=16.8, 7.7 Hz, 1H), 2.98 (m, 2H), 2.44 (t, J=7.3 Hz, 2H), 2.01 (bd, J=15.0 Hz, 2H), 1.93 (m, 3H), 1.80 (m, 2H), 1.44 (m, 2H).
EXAMPLE 9 erythro- and-threo-3-[3-[4-[(piperidin-4-yl)methoxy]phenyl]isoxazolin-5-yl{[butanesulfonyl]amino]propionate, Trifluoroacetic Acid Salt
Part A. Dicyclohexylammonium d,l-2-[(Butanesulfonyl)-aminol-4-pentenoic acid,
To a suspension of d,l-2-amino-4-pentenoic acid (2.54 g, 22.06 mmol) in acetonitrile (35 mL) was added BSTFA (7.3 mL, 27.5 mmol). The suspension was heated at 55° C. for 2 hours, after which time a golden yellow solution resulted. To this solution was added pyridine (2.2 mL, 27.2 mmol) and n-butanesulfonyl chloride (3.0 mL, 23.1 mmol). The mixture was heated at 70° C. for 20 hours, then cooled to room temperature. Concentration in vacuo afforded a brown oil, to which was added 15% KHSO4 (5 mL). The mixture was stirred for 1 hour and shaken with EtOAc (3x). The combined organic extracts were washed with sat. NaCl, dried (MgSO4), concentrated and the resulting oil dissolved in ether (5 mL). To this solution was added DCHA (4.38 mL, 22.0 mmol), causing immediate precipitation of the dicyclohexylammonium salt. The solid was collected by filtration and pumped to constant weight, giving 8.42 g (92%); mp: 207.1-208.6° C.; 1 H NMR (400 MHz, MeOH-d4) δ 5.84 (m, 1H), 5.09 (dm, J=17.1.Hz, 1H), 5.04 (dm, J=10.2 Hz, 1H), 3.80 (dd, J=7.1, 5.1 Hz, 1H), 3.18 (m, 2H), 3.02 (m, 2H), 2.49 (m, 2H), 2.06 (m, 4H) , 1.78 (m, 8H), 1.55 (m, 12H), 0.94 (t, J=7.3 Hz).
Part B. Methyl d,l-2-[(Butanesulfonyl)amino]-4-pentenoate
To a solution of dicyclohexylammonium d,l-2-[(butanesulfonyl)amino]-4-pentenoate (8.36 g, 20.07 mmol) in MeOH (50 mL) was added HCl-saturated MeOH (50 mL). The resulting suspension was stirred at room temperature for 18 hours, diluted with ether, and filtered. Concentration of the filtrate in vacuo was followed by the addition of ether, a second filtration, and washing of the filtrate with 0.1M HCl, sat. NaHCO3, sat. NaCl. The solution was dried over anhydrous MgSO4, concentrated and placed under vacuum until constant weight to give 4.49 g (90%) of the desired ester as a light brown oil; 1 H NMR (300 MHz, CDCl3) δ 5.68 (m, 1H), 5.19 (bd, J=1.5 Hz, 1H), 5.15 (m, 1H), 4.78 (bd, J=8.4 Hz, 1H), 4.20 (dt, J=8.8, 5.8 Hz, 1H), 3.77 (s, 3H), 2.99 (m, 2H), 2.54,(t, J=6.6 Hz, 2H), 1.76 (m, 2H), 1.42 (sextuplet, J=7.3 Hz, 2H), 0.93 (t, J=7.3 Hz, 3H)
Part C. Methyl erythro- and-threo-3-(3-[4-{(Butyloxycarbonylpiperidin-4-yl)methoxy}phenyl]isoxazolin-5-yl{(butanesulfonyl]amino})propionate
To a solution of 4-[(N-t-butyloxycarbonylpiperidin-4-yl)methoxy]benzaldoxime (2.680 g, 8.01 mmol), methyl d,l-2-[(butanesulfonyl)amino]-4-pentenoate (2.000 g, 8.02 mmol) and TEA (0.11 mL, 0.79 mmol) in THF (10 mL) was added a 5% solution of NaOCl (common household bleach, 15 mL, 10.5 mmol). The resulting mixture was rapidly stirred at room temperature for 20 hours. The mixture was diluted with EtOAc and water and the layers were separated. The aqueous portion was washed with EtOAc, and the combined organic fraction washed with sat. NaCl and dried over MgSO4. Concentration in vacuo afforded a light brown oil (4.8 g), which was purified using flash chromatography (0-50% EtOAc/hexanes in 5 steps), giving four components. The least polar of these materials (fractions 8-11) was determined by 1 H NMR to be the starting olefin (1.520 g, 76%). The next component isolated in order of increasing polarity (fractions 12-15) was determined by 1 H NMR to be the starting oxime (1.423 g, 53%). The next component off of the column (fraction 20) was determined to be the faster of the two diastereomers (317 mg). This material had co-eluted with an impurity having a 1 H NMR profile similar to the starting oxime and appeared to be approximately 50% pure. The most polar component isolated (fractions 22-25) was assigned as the second diastereomer (395 mg, 8%); mp:.127.5-129.3° C.; 1 H NMR (300 MHz, CDCl3) δ 7.56 (d, J=8.6 Hz, 2H) , 6.87 (d, J=8.6 Hz, 2H), 5.25 (d, J=9.5 Hz, 1H), 4.87 (m, 1H), 4.35 (dt, J=9.2, 3.7 Hz, 1H), 4.15 (bs, 2H), 3.81, (d, J=6.2 Hz, 2H), 3.78 (s, 3H), 3.49 (dd, J=16.5, 10.3 Hz, 1H), 3.05 (t, J=7.7 Hz, 2H), 2.97 (dd, J=16.5, 7.0 Hz, 1H), 2.73 (bt, J=12.1 Hz, 2H), 2.21 (m, 1H), 1.94 (m, 2H), 1.82 (m, 4H), 1.45 (s, 9H), 1.24 (m, 3H), 0.92 (t, J=7.3 Hz, 3H).
Part D. 3-(3- [4-{(Butyloxycarbonylpiperidin-4-yl)methox-y}phenyl]isoxazolin-5-yl{[butanesulfonyl]amino})-propionic Acid (More Polar Diastereomer)
A solution of methyl 3-(3-[4-{(butyloxycarbonylpiperidin-4-yl)methoxy}phenyl]isoxazolin-5-yl{[butanesulfonyl]amino})propionate more polar diastereomer (200 mg, 0.344 mmol) in THF (1 mL) was saponified using 0.5M LiOH (1 mL, 0.5 mmol) over 4 hours as per Example 1, Part F. The crude carboxylic acid was crystallized from EtOAc/hexanes, affording 77 mg (39%) of the desired material; mp: 137.3-139.0° C.; 1 H NMR (300 MHz, CDCl3) δ 7.55 (d, J=8.8 Hz, 2H), 6.87 (d, J=8.8 Hz, 2H), 5.45 (d, J=9.5 Hz, 1H), 4.92 (m, 1H), 4.37 (m, 1H), 4.15 (b, 2H), 3.81, (d, J=6.2 Hz, 2H), 3.47 (dd, J=16.5, 9.9 Hz, 1H), 3.08 (t, J=8.1 Hz, 2H), 3.01 (dd, J=16.5, 7.0 Hz, 1H), 2.74 (bt, J=12.1 Hz, 2H), 2.26 (m, 1H), 2.01 (m, 2H), 1.81 (m, 4H), 1.45 (s, 9H, overlapped with m, 1H), 1.24 (m, 3H) , 0.91 (t, J=7.3 Hz, 3H).
Part D'. 3-(3-[4-{(Butyloxycarbonylpiperidin-4-yl)methoxy}phenyl]isoxazolin-5-yl{[butanesulfonyl]amino})-propionic Acid (Less Polar Diastereomer)
A solution of the impure methyl 3-(3-[4-{(butyloxycarbonylpiperidin-4-yl)methoxy}phenyl]isoxazolin-5-yl{[butanesulfonyl]amino})propionate less polar diastereomer (309 mg) in THF (5 mL) was saponified using 0.5M LiOH (2 mL, 1 mmol) over 6 hours as per Example 1, Part F. The crude carboxylic acid was purified using flash chromatography (CHCl3 --5-15% MeOH/CHCl3 step gradient) followed by crystallization from EtOAc/hexanes, affording 169 mg of the desired material; mp: 155° C. (dec); 1 H NMR (400 MHz, DMSO-d6, 80° C.) δ 7.56 (d, J=8.8 Hz, 2H), 6.98 (d, J=8.8 Hz, 2H), 4.80 (m, 1H), 3.96 (bd, J=13.2 Hz, 2H), 3.90 (d, J=6.3 Hz, 2H), 3.77 (bs, 3H), 3.52 (t, J=7.8 Hz, 1H), 3.38 (dd, J=14.4, 10.0 Hz, 1H), 2.98 (t, J=7.8 Hz, 2H), 2.76 (dt, J=12.2, 1.7 Hz, 2H), 1.95 (m, 2H), 1.75 (m, 4H), 1.41 (s, 9H), 1.38 (d, J=7.6 Hz, 1H), 1.25 (m, 4H), 0.88 (t, J=7.3 Hz, 3H).
Part E. 3-(3-[4-{(Piperidin-4-yl)methoxy}phenyl]isoxazolin-5-yl{[butanesulfonyl]amino})propionic Acid, Trifluoroacetic Acid Salt (More Polar Diastereomer)
3-(3-[4-{(Butyloxycarbonylpiperidin-4-yl)methoxy}phenyl]isoxazolin-5-yl{[butanesulfonyl]amino})propionic acid more polar diastereomer(40 mg, 0.070 mmol) was Boc-deprotected using 33% TFA/DCM according to Example 1, Part G. Recrystallization from methanol then afforded 4 mg (10%) of the TFA salt; mp: 263.5° C. (dec).
Part E'. 3-(3-[4-{(Piperidin-4-yl)methoxy}phenyl]isoxazolin-5-yl{[butanesulfonyl]amino}propionic Acid, Trifluoroacetic Acid Salt (Less Polar Diastereomer)
3-(3-[4-{(Butyloxycarbonylpiperidin-4-yl)methoxy}phenyl]isoxazolin-5-yl{[butanesulfonyl]amino})propionic acid less polar diastereomer(98 mg, 0.173 mmol) was Boc-deprotected using 33% TFA/DCM according to Example 1, Part G, giving 40 mg of the TFA salt. Recrystallization from methanol then afforded 28 mg (29%) of the pure amino acid; mp: 239.4-240.7° C.
EXAMPLE 33 4-Carboxymethyl-3-[4- (2-piperidin-4-yl)ethoxyphenyl]-(5R,S)-isoxazolin-5-ylacetic Acid, Trifluoroacetic Acid Salt
This material was prepared analogously to Example 1, giving the desired material; mp: 141.4° C. (dec); 1 H NMR (400 MEz, CD3 OD, 60° C.) δ7.60 (d, J=8.8 Hz, 2H), 6.96 (d, J=8.8 Hz, 2H), 3.84 (d, J=17.3 Hz, 1H), 3.66 (s, 3H), 3.59 (d, J=17.3 Hz, 1H), 3.38 (bd, J=12.9 Hz, 1H), 3.24 (t, J=1.7 Hz, 2H), 3.21 (dm, J=20.3 Hz, 1H), 3.04 (d, J=1.5 Hz, 2H), 3.00 (dt, J=12.9, 2.9 Hz, 2H), 2.02 (bd, J=14.4 Hz, 2H), 1.95 (m, 1H), 1.81 (m, 2H), 1.48 (m, 2H).
EXAMPLE 43 N-[3-(4-Amidinophenyl)isoxazolin-5(R,S)-ylacetyl]-(R,S)-3-amino-3-phenylpropanoic Acid
Part A: 4-Cyanobenzaldoxime
This material was prepared from 4-cyanobenzaldehyde according to Kawase and Kikugawa (J. Chem. Soc., Perkin Trans I 1979, 643). To a solution of 4-cyanobenzaldehyde (1.31 g, 10 mmol) in 1:1 EtOH:pyridine (10 mL) was added hydroxylamine hydrochloride (0.70 g, 10 mmol). The resulting solution was stirred at room temperature for 18 h and was concentrated in vacuo to one-half volume. To this solution was added ice water, causing the product to crystallize from solution. Recrystallization from EtOH--water followed by drying over P2 O5 afforded 1.46 g (100%) of the desired oxime; mp: 167.8-169.4° C.
Part B: Methyl 3-(3-Butenoyl)amino-3-phenylpropionate
To a solution of vinylacetic acid (861 mg, 10.0 mmol), methyl 3-amino-3-phenylpropionate hydrochloride (2.37 g, 11.0 mmol) and TEA (1.6 mL, 12 mmol) in DCM (20 mL) at -10° C. was added DEC (2.11 g, 11.0 mmol). The resulting mixture was stirred at -10° C. for 15 hours. The mixture was then washed with water, 0.1 M HCl, sat. NaHCO3, sat. NaCl and dried over anhydrous MgSO4. Concentration in vacuo followed by pumping until constant weight gave 2.36 g (95%) of the desired amide as a golden oil of suitable purity for further reaction; 1 H NMR (300 MHz, CDCl3) δ7.28 (m, 5H), 6.78 (bd, J=7.7 Hz, 1H), 5.95 (m, 1H), 5.43 (dt, J=8.4, 5.9 Hz, 1H), 5.25 (m, 2H), 3.61 (s, 3H), 3.04 (d, J=7.0 Hz, 2H), 2.88 (dq, J=15.0, 5.9 Hz, 2H).
Part C: Methyl 3(R,S)-{5(R, S)-N-[3-(4-Cyanophenyl)isoxazolin-5-ylacetyl]amino)-3-phenylpropanoate
To a solution of methyl 3-(3-butenoyl)amino-3-phenylpropionate (816 mg, 3.30 mmol) and 4-cyanobenzaldoxime (prepared according to Example 1, Part A, 438 mg, 3.00 mmol) in CH2 Cl2 (10 mL) was added a 5% solution of sodium hypochlorite ("Clorox", 5.3 mL, 3.5 mmol). The resulting mixture was stirred rapidly overnight (15 h), the layers separated and the aqueous washed with CH2 Cl2. The combined organic was dried (MgSO4) and concentrated in vacuo. The crude product was then purified using flash chromatography (70% EtOAc/hexanes), affording 731 mg (62%) of the desired isoxazoline as a 1:1 mixture of diastereomers; 1 H NMR (300 MHz, CDCl3) δ7.74 (m, 8H), 7.29 (m, 10H), 6.92 (bm, 2H), 5.42 (m, 2H), 5.16 (m, 2H), 3.64 (s, 3H), 3.60 (s, 3H), 3.48 (m, 2H), 3.26 (dd, J=17.3, 7.7 Hz, 1H), 3.15 (dd, J=16.8, 8.1 Hz, 1H), 2.85 (m, 2H), 2.69 (m, 2H).
Part D: Methyl 3(R,S)-{5(R,S)-N-[3-(4-Amidinophenyl)isoxazo-lin-5-ylacetyl]amino}-3-phenylpropanoate
Into a solution of methyl 3(R,S)-{5(R,S)-N-[3-(4-cyanophenyl)isoxazolin-5-ylacetyl]amino}-3-phenylpropanoate (587 mg, 1.50 mmol) in 10% DCM/methanol (55 mL) was bubbled dry HCl gas for 2 hours. The mixture was stirred for 18 hours, then concentrated in vacuo. The crude imidate was dissolved in methanol (20 mL) and ammonium carbonate added. The resulting mixture was stirred for 18 hours, then filtered. The filtrate was concentrated in vacuo and the residue purified using flash chromatography (CHCl3 --20% methanol/CHCl3). Concentration of the appropriate fractions in vacuo followed by placing the residue under vacuum until constant weight afforded 193 mg (32%) of the desired amidines; CIMS (NH3, e/z, relative abundance): 409 (M+H)+, 100%.
Part E: 3(R,S)-{5(R,S)-N-[3-(4-Amidinophenyl)isoxazolin-5-ylacetyl]amino}-3-phenylpropanoic Acid, Trifluoroacetic Acid Salt
Methyl 3(R,S)-{5(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-ylacetyl]amino}-3-phenylpropanoate (45 mg, 0.113 mmol) was saponified using 0.5 M LiOH (0.6 mL, 0.3 mmol) according to Example 1, Part F, affording 28 mg (49%); CIMS (NH3, e/z, relative abundance): 412 (M+H)+, 100%.
EXAMPLE 43A 5(R,S)-N-[3-(4-Amidinophenyl)isoxazolin-5-ylacetyl]aminopropanoic Acid
Part A: Ethyl 3-(3-Butenoyl)aminopropionate
To an ice cold solution of vinylacetic acid (4.39 g, 51.0 mmol), ethyl 3-aminopropionate hydrochloride (8.49 g, 55.3 mmol) and TEA (7.8 mL, 56 mmol) in DCM (50 mL) was added DEC (10.54 g, 55.0 mmol). The resulting mixture was warmed to room temperature overnight (18 h). The mixture was then washed with water, 0.1 M HCl, sat. NaHCO3, sat. NaCl and dried (MgSO4). Concentration in vacuo followed by pumping until constant weight was achieved gave 6.34 g (67%) of the desired amide as a golden oil of purity suitable for further reaction; 1 H NMR (300 MHz, CDCl3) δ6.26 (bs, 1H), 5.98-5.85 (m, 1H), 5.25-5.17 (m, 2H), 4.16 (q, J=7.0 Hz, 2H), 3.52 (q, J=5.9 Hz, 2H), 2.99 (dt, J=7.0, 1.1 Hz, 2H), 2.53 (t, J=5.9 Hz, 2H), 1.27 (t, J=7.0 Hz, 3H).
Part B: Ethyl 5(R,S)-N-[3-(4-Cyanophenyl)isoxazolin-5-ylacetyl]aminopropanoate
To a solution of ethyl 3-(3-butenoyl)aminopropionate (556 mg, 3.00 mmol) and 4-cyanobenzaldoxime (prepared according to Example 1, Part A, 292 mg, 2.00 mmol) in CH2 Cl2 (7 mL) was added a 5% solution of sodium hypochlorite ("Clorox", 4.2 mL, 2.8 mmol). The resulting mixture was stirred rapidly overnight (15 h), the layers separated and the aqueous washed with CH2 Cl2. The combined organic was dried (MgSO4) and concentrated in vacuo. The crude product was then purified using flash chromatography (EtOAc), affording 386 mg (58%) of the desired isoxazoline; mp: 102.0-102.9° C.
Part C: Ethyl 5(R,S)-3-[3-(4-Amidinophenyl)isoxazolin-5-ylacetyl]aminopropanoate
Into a solution of ethyl 5(R,S)-3-[3-(4-cyanophenyl)isoxazolin-5-ylacetyl]aminopropanoate (1.65 mg, 5.00 mmol) in 10% DCM/EtOH (165 mL) was bubbled HCl gas for 2 hours. After 18 hours, the solvent was evaporated in vacuo, the residue dissolved in EtOH (100 mL) and ammonium carbonate (14.41 g, 150 mmol) added. The resulting suspension was stirred at room temperature for 18 hours, then filtered and the resulting filtrate concentrated in vacuo. The residue was then crystallized from EtOH/ether, giving 713 mg (41%) of the desired amidine; 1 H NMR (300 MHz, CD3 OD) δ7.88 (AB quartet, Δ=16.8 Hz, J=8.4 Hz, 4H), 5.13 (m, 1H), 4.12 (q, J=7.3 Hz, 2H), 3.58 (dd, J=17.2, 10.6 Hz, 1H), 3.44 (m, 2H), 3.26 (dd, J=17.2, 7.3 Hz, 1H, coincident with solvent), 2.57 (m, 4H), 1.25 (t, J=7.3 Hz, 2H).
Part H: 5(R,S)-3-[3-(4-Amidinophenyl)isoxazolin-5-ylacetyl]aminopropanoic Acid
To a solution of ethyl 5(R,S)-3-[3-(4-amidinophenyl)isoxazolin-5-ylacetyl]aminopropanoate (346 mg, 1.00 mmol) in EtOH (6 mL) was added 0.5 M LiOH. Upon mixing, a precipitate of the zwitterionic product began to form. After stirring for 18 hours at room temperature, the solid was collected by filtration, affording 365 mg of the title compound; 1 H NMR (300 MHz, CD3 OD) δ7.86 (AB quartet, Δ=18.3 Hz, J=8.4 Hz, 4H), 5.21 (m, 1H), 3.57 (dd, J=17.2, 10.6 Hz, 1H), 3.43 (m, 2H), 3.25 (dd, J=17.2, 7.3 Hz, 1H, coincident with solvent), 2.64 (dd, J=14.6, 6.8 Hz, 1H), 2.52 (m, 3H).
EXAMPLE 120a Methyl 3 (R)-{5(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-ylacetyl]amino}-3-phenethylpropanoate
Part A. Methyl (E)-5-phenyl-2-pentenoate
A solution of hydrocinnamaldehyde (13.42 g, 0.1 mol) and methyl(triphenylphosphoranylidene)acetate (33.44 g, 0.1 mol) in THF was stirred at reflux for 20 hours. The reaction mixture was concentrated under vacuum and the residue was purified by flash chromatography using hexane:EtOAc::9:1. The desired product was obtained as a clear, pale yellow oil (8.0 g, 0.042 mol, 42%); 1 H NMR (300 MHz, CDCl3) δ 7.3-7.2 (m, 2H), 7.2-7.1 (m, 3H), 7.1-6.9 (m, 1H), 5.85 (d, 1H, J=5.8 Hz), 3.75 (s, 3H), 2.8 (t, 2H, J=7.7 Hz), 2.55 (q, 2H, J=7.4 Hz); MS (NH3 -DCI) 191 (M+H)+.
Part B. Methyl 3-(R)-[N-(1-(R)-1-phenylethyl)amino]-5-phenylpentanoate
A mixture of methyl (E)-5-phenyl-2-pentenoate (5.70 g, 0.03 mol) and R-methylbenzylamine (14.54 g, 0.12 mol) was heated at 110° C. over 94 hours. The cooled reaction mixture was purified by flash chromatography using hexane:EtOAc::8:2 to afford 1.18 g (0.0038 mol, 12%) of the desired product as a clear liquid; 1 H NMR (300 MHz, CDCl3) δ7.4-7.0 (m, 11H), 3.9 (q, 1H, J=6.5 Hz), 3.65 (s, 3H), 2.9-2.65 (m, 2H), 2.6-2.35 (m, 3H), 1.75-1.6 (m, 2H), 1.35 (d, 3H, J=6.2 Hz); MS (NH3 -DCI) 312 (M+H)+.
Part C. Methyl 3-(R)-amino-5-phenylpentanoate  acetic acid salt
A mixture of methyl,3-(R)-[N-(1-(R)-1-phenylethyl)amino]-5-phenylpentanoate (0.72 g, 2.3 mmol), 20% Pd(OH)2 /C (0.38 g), cyclohexene (8.2 mL), glacial HOAc (0.13 mL, 2.3 mmol), and MeOH (15 mL) was heated at reflux under N2 for 20 hours. After cooling, the catalyst was removed by filtration through a Celite plug, rinsed with MeCH, and the solution concentrated under vacuum. The residue was triturated with hexane to afford 0.46 g (96%) of a white solid, mp=73-75° C.; 1 H NMR (300 MHz, DMSO) δ8.3 (bs, 2H), 7.35-7.15 (m, 5H), 3.65 (s, 3H), 3.45-3.35 (m, 1H), 2.8-2.6 (m, 4H), 2.0-1.7 (m, 2H); [α]D 25 --12.50° (c=0.0032, MeOH).
Part D. Methyl 3(R)-{5(R,S)-N-[3-(4-cyanophenyl)isoxazolin-5-ylacetyl]amino}-3-phenethylpropanoate
To a suspension of 3-(4-cyanophenyl)isoxazolin-5-ylacetic acid (460 mg, 2.0 mmol) in EtOAc (15 ml) was added methyl 3-(R)-amino-5-phenylpentanoate acetic acid salt (410 mg, 2.0 mmol), TBTU (640 mg, 2.0 mmol), and Et3 N (0.56 mL, 400 mg, 4.0 mmol). After stirring at room temp for 16 hours, the reaction mixture was concentrated under vacuum then purified by flash chromatography using EtOAc to afford 690 mg (83%) of a colorless oil. 1 H NE (300 MHz, DMSO) δ 8.05 (brs, 1H), 7.95-7.9 (m, 2H), 7.85-7.8 (m, 2H), 7.3-7.25 (m, 2H), 7.2-7.1 (m, 2H), 5.15-5.0 (m, 1H), 4.15-4.0 (m, 1H), 3.6 (d, 3H, J=9.9 Hz), 3.3 (d, 2H, J=6.9 Hz), 3.25-3.15 (m, 1H), 2.75-2.35 (m, 6H), 1.8-1.6 (m, 2H); MS (NH3 -DCI) 420 (M+H)+.
Part E Methyl 3(R)-{5(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-ylacetyl]amino}-3-phenethylpropanoate
This material was prepared from methyl 3(R)-{5(R,S)-N-[3-(4-cyanophenyl)isoxazolin-5-ylacetyl]amino}-3-phenethylpropanoate (670 mg, 1.6 nmol) according to Example 43, Part D. The crude product was triturated with cold ether to afford 272 mg (39%) of a white solid of the title compound as a 1:1 mixture of diastereomers, mp=76-78° C.; 1 H NMR (300 MHz, DMSO) δ 8.1-8.0 (m, 1H), 8.0-7.8 (m, 4H), 7.95-7.85 (m, 5H), 7.35-7.2 (m, 5H), 5.1-5.0 (m, 1H), 4.1-4.0 (m, 1H), 3.6 (s, 3H), 3.3-3.15 (m, 2H), 2.7-2.4 (m, 6H), 1.8-1.7 (m, 2H), 1.1-1.0 (m, 2H); Mass Spectrum (NH3 -ESI,) 437 (M+H)+.
EXAMPLE 120b Methyl 3(S)-{5(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-ylacetyl]amino}-3-phenethylpropanoate
Part A. Methyl 3-(S)-[N-(1-(R)-1-phenylethyl)amino]-5-phenylpentanoate
A mixture of (E)-methyl-5-phenyl-2-pentenoate (5.70 g, 0.03 mol) and R-methylbenzylamine (14.54 g, 0.12 mol) was heated at 110° C. over 94 hours. The cooled reaction mixture was purified by flash chromatography using hexane:EtOAc::8:2 to afford 1.20 g (0.0039 mol, 13%) of the desired product as a clear liquid; 1 H NMR (300 MHz, CDCl3) δ 7.35-7.0 (m, 11H), 3.9 (q, 1H, J=6.6 Hz), 3.65 (s, 3H), 2.95-2.8 (m, 1H), 2.75-2.5 (m, 2H), 2.45-2.35 (m, 2H), 1.9-1.65 (m, 2H), 1.3 (d, 3H, J=6.6 Hz); MS (NH3 -DCI) 312 (M+H)+.
Part B. Methyl 3-(S)-amino-5-phenylpentanoate  acetic acid salt
Methyl 3-(S)-[N-benzyl-N-(1-(R)-1-phenylethyl)amino]heptanoate (0.93 g, 2.9 mmol), 20% Pd(OH)2 /C (0.47 g), cyclohexene (10.1 mL), glacial HOAc (0.17 mL, 2.9 mmol), and MeOH (20 mL) were heated at reflux under N2 for 48 hours. After cooling, the catalyst was removed by filtration through a Celite plug, rinsed with MeOH, and the solution concentrated under vacuum. The residue was triturated with hexane to afford 0.65 g (80%) of a white solid, mp=86-88° C.; 1 H NMR (300 MHz, CDCl3) δ 7.35-7.15 (m, 5H), 5.3 (brs, 2H), 3.65 (s, 3H), 3.35-3.2 (m, 1H), 2.8-2.55 (m, 3H), 2.5-2.4 (m, 1H), 2.0 (s, 3H), 1.8 (q, 2H, J=7.4 Hz); [α]D25 +9.55° (c=0.220, MeOH).
Part C. Methyl 3(S-{5(R,S)-N-[3-(4-cyanophenyl)isoxazolin-5-ylacetyl]amino}-3-phenethylpropanoate
To a suspension of 3-(4-cyanophenyl)isoxazolin-5-ylacetic acid (700 mg, 2.6 mmol) in EtOAc (15 ml) was added methyl 3-(S)-amino-5-phenylpentanoate acetic acid salt (600 mg, 2.6 mmol), TBTU (830 mg, 2.6 mmol), and Et3 N (1.09 mL, 790 mg, 7.8 mmol). After stirring at room temperature 16 hours, the reaction mixture was concentrated under vacuum then purified by flash chromatography using EtOAc to afford 420 mg (38%) of a colorless oil. 1 H NMR (300 MHz, CDCl3) δ 8.05-8.0 (m, 1H), 7.95-7.9 (m, 2H), 7.85-7.8 (m, 2H), 7.3-7.2 (m, 2H), 7.2-7.1 (m, 3H), 5.15-5.0 (m, 1H), 4.15-4.0 (m, 1H), 3.6-3.55 (m, 3H), 3.3-3.1 (m, 1H), 2.7-2.4 (m, 6H), 1.8-1.6 (m, 2H); MS (NH3 -DCI) 420 (M+H)+.
Part D. Methyl 3(S)-{5(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-ylacetyl]amino}-3-phenethylpropanoate
This material was prepared from methyl 3(S)-{5(R,S)-N-[3-(4-cyanophenyl)isoxazolin-5-ylacetyl]amino}-3-phenethylpropanoate (360 mg, 0.86 mmol) according to Example 43, Part D. The crude product was triturated with cold ether to afford 230 mg (62%) of an amorphous solid of the title compound as a 1:1 mixture of diastereomers, mp=84-86° C.; 1 H NMR (300 MHz, DMSO) δ 8.1-8.0 (m, 1H), 8.0-7.8 (m, 4H), 7.75-7.7 (m, 1H), 7.3-7.1 (m, 6H), 5.1-5.0 (m, 1H), 4.15-4.0 (m, 1H), 3.65 (s, 3H), 3.3-3.1 (m, 1H), 2.7-2.6 (m, 3H), 2.5-2.4 (m, 3H), 1.8-1.65 (m, 2H), 1.1-1.0 (m, 2H); Mass Spectrum (NH3 -ESI) 437 (M+H)+.
EXAMPLE 189 5(R,S)-(2-Piperidin-4-yl)ethyl-8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro[4,4]non-2-ene-7,9-dione
Part A. 3-(N-t-Butyloxycarbonylpiperidin-4-yl)propanal
To a suspension of PCC (11.52 g, 53.44 mmol) and sodium acetate (4.38 g, 53.4 mmol) in DCM (60 mL) was added a solution of 3-(N-t-butyloxycarbonylpiperidin-4-yl)propanol (10.00 g, 41.09 mmol) in DCM (20 mL). After 4 hours at room temperature, the mixture was diluted with ether and passed though a short column of fluorisil® using ether as an eluent. The eluate was concentrated in vacuo and placed under vacuum until constant weight was achieved, affording 8.32 g (84%) of the desired aldehyde as a colorless oil; 1 H NMR (300 MHz, CDCl3) δ 9.76 (t, J=1.5 Hz, 1H), 4.05 (bs, 2H), 2.64 (bt, J=11.7 Hz, 2H), 2.45 (dt, J=7.3, 1.5 Hz, 2H), 1.60 (m, 3H), 1.43 (s, 9H, overlapped with m, 2H), 1.08 (dq, J=12.1, 4.0 Hz, 2H).
Part B. (E,Z)-3-(N-t-Butyloxycarbonylpiperidin-4-yl)propanal Oxime
To a solution of 3-(N-t-butyloxycarbonylpiperidin-4-yl)propanal (3.905 g, 16.18 mmol) in EtOH : pyr=1:1 (20 mL) was added hydroxylamine hydrochloride (1.701 g, 24.48 mmol) and the resulting solution stirred at room temperature for 20 hours. Concentration in vacuo, resulted in an oil, which was dissolved in EtOAc and washed with 0.1 M HCl (3x), water, sat. CUSO4 (2x), water and brine. The solution was dried over MgSO4, concentrated in vacuo and placed under vacuum until constant weight was achieved, affording 4.071 g (98%) of a 1:1 mixture of the (E,Z)-oxime as a colorless oil; 1 H NMR (300 MHz, CDCl3) δ 7.42 (t, J=6.2 Hz, 0.5H), 6.70 (t, J=5.5 Hz, 0.5H), 4.06 (bs, 2H), 2.67 (bt, J=12.8 Hz, 2H), 2.41 (m, 1H), 2.23 (m, 1H), 1.66 (b, 2H), 1.45 (s, 9H, overlapped with m, 4H), 1.08 (m, 2H).
Part C. Methyl (5R,S)-3-{[2-(N-t-Butyloxycarbonylpiperidin-4-yl)ethyl]-5-carboxymethylisoxazolin-5-yl}acetate
To a solution of (E,Z)-3-(N-t-butyloxycarbonylpiperidin-4-yl)propanal oxime (503 mg, 1.96 mol) and dimethyl itaconate (620 mg, 3.92 mmol) in DCM (3 mL) was added a 5% solution of sodium hypochlorite (common household bleach, 3 mL, 2 mmol). The resulting mixture was stirred overnight (19 hours) at room temperature. The layers were separated and the aqueous washed with DCM (2x). The combined DCM fraction was dried over MgSO4 and concentrated in vacuo. Purification using flash chromatography (hexanes--10% EtOAc/hexanes--50% EtOAc/hexanes) followed by concentration and pumping to constant weight afforded the desired isoxazoline (510 mg, 63%) as a colorless oil; 1 H NMR (300 MHz, CDCl3) δ 4.06 (bd, J=13.6 Hz, 2H), 3.78 (s, 3H), 3.67 (s, 3H), 3.57 (d, J=17.6 Hz, 1H), 3.15 (d, J=16.5 Hz), 3.06 (d, J=17.6 Hz, 1H), 2.86 (d, J=16.5 Hz, 1H), 2.65 (bt, J=12.1 Hz, 2H), 2.36 (m, 2H), 1.65 (m, 2H, overlapped with H2 O, 2H), 1.43 (s, 9H), 1.07 (m, 2H).
Part D. (5R,S)-3-{[2-(N-t-Butyloxycarbonylpiperidin-4-yl)ethyl]-5-carboxyisoxazolin-5-yl}acetic Acid
To a solution of methyl (5R,S)-3-{[2-(N-t-butyloxycarbonylpiperidin-4-yl)ethyl]-5-carboxymethylisoxazolin-5-yl}acetate (380 mg, 0.921 mmol) was saponified using 0.5M LiOH (5 mL, 2.5 mmol) in THF (5 mL). The reaction was stirred at ambient temperature for 5 hours, according to Example 1, Part F to give 240 mg (68%) of the diacid; mp: 154.4-154.9° C.; 1 H NMR (300 MHz, MeOH-d4) δ 4.04 (bd, J=13.2 Hz, 2H), 3.52 (d, J=17.8 Hz, 1H), 3.18 (d, J=17.8 Hz, 1H), 2.97 (AB quartet, Δ=32.6, J=16.8 Hz, 2H), 2.72 (b, 2H), 2.39 (m, 2H), 1.71 (bd, J=13.2 Hz, 2H), 1.51 (m, 3H), 1.43 (s, 9H), 1.05 (m, 2H).
Part E. 5(R,S)-2-(N-t-Butyloxycarbonylpiperidin-4-yl)ethyl-8-[(2-(1,1-dimethylethoxycarbonyl)ethyl]-1-oxa-2,8-diazaspiro[4,4]non-2-ene-7,9-dione
To a solution of (5R,S)-3-{[2-(N-t-butyloxycarbon-ylpiperidin-4-yl)ethyl]-5-carboxyisoxazolin-5-yl}acetic acid (700 mg, 1.82 mmol) in THF (5 mL) was added DCC (378 mg, 1.83 mmol), and the resulting suspension was stirred for 30 min at room temperature. To this mixture was added a suspension of β-alanine t-butyl ester hydrochloride (372 mg, 2.05 mmol) and TEA (300 μL, 2.15 mmol) in THF (5 mL). The mixture was stirred overnight (18 hours) at room temperature. Following dilution with EtOAc, the mixture was filtered and the filtrate washed with 0.1M HCl, sat. NaHCO3 and sat. NaCl. It was dried over anhydrous MgSO4, concentrated and placed under vacuum until constant weight was reached, giving 430 mg (46%) of the crude amide. A portion of this material (420 mg, 0.821 mmol) was dissolved in THF (4 mL). To this solution was added HOSuc (100 mg, 0.869 mmol) followed by DCC (180 mg, 0.872 mmol). The resulting suspension was stirred at room temperature for 18 hours. Following dilution with ether, the mixture was cooled to 0° C. and filtered. The filtrate was dried over anhydrous MgSO4, concentrated and placed under vacuum until constant weight was reached, giving 430 mg (86%) of the crude active ester. A portion of this material (402 mg, 0.660 mmol) was dissolved in DMF (5 mL) at 0° C. To this solution was added NaH (16 mg, 0.66 mmol). After 3 hours at 0° C., the reaction was quenched with HOAc. After dilution with EtOAc, the mixture was washed with water (4x), sat. NaHCO3, water, 0.1M HCl and sat. NaCl. It was dried over anhydrous MgSO4, concentrated and placed under vacuum until constant weight was reached, giving 230 mg (70%) of the crude imide. The crude material was purified using flash chromatography (CHCl3 --5% MeOH/CHCl3), affording 149 mg (46%) of a colorless oil after concentration of the appropriate fractions and pumping to constant weight; 1 H NMR (300 MHz, CDCl3) δ 4.09 (b, 2H) , 3.82 (t, J=7.3 Hz, 2H), 3.54 (d, J=17.2 Hz, 1H), 3.12 (d, J=18.7 Hz, 1H), 2.98 (d, J=17.2 Hz, 1H), 2.83 (d, J=18.7 Hz, 1H), 2.69 (m, 2H), 2.57 (t, J=7.3 Hz, 2H), 2.42 (m, 2H), 1.68 (m, 2H), 1.57 (m, 2H), 1.45 (s, 9H, coincident with m, 1H), 1.11 (m, 2H).
Part F. 5(R,S)-(2-Piperidin-4-yl)ethyl-8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro[4,4]non-2-ene-7,9-dione
To a solution of 5(R,S)-2-(N-t-butyloxycarbonylpiperidin-4-yl)ethyl-8-[(2-(1,1-dimethylethoxycarbonyl)ethyl]-1-oxa-2,8-diazaspiro[4.4]non-2-ene-7,9-dione (75 mg, 0.152 mmol) in DCM (1 mL) was added TFA (0.5 mL, 8 mmol). The reaction was stirred at room temperature for 2 hours, then was concentrated in vacuo. Excess TFA was chased by rotary evaporation with toluene (2x). Crystallization from MeOH/ether gave 10 mg (15%) of the desired amino acid after pumping to constant weight; mp: 178.0-179.1° C.; 1 H NMR (400 MHz, DMSO-d6, 60° C.) δ 12.15 (bs, 1H). 8.26 (bs, 2H), 3.64 (m, 2H), 3.39 (d, J=17.8 Hz, 1H), 3.26 (m, 3H), 2.98 (AB quartet, Δ=71.3 Hz, J=18.3 Hz, 2H), 2.85 (m, 2H), 2.50 (m, 1H, coincident with DMSO-d5), 2.37 (t, J=7.6 Hz, 2H), 1.84 (bd, J=11.7 Hz, 2H), 1.58 (m, 1H), 1.52 (t, J=7.6 Hz, 2H), 1.29 (m, 2H).
EXAMPLE 275 N3 -[3-(4-amidinophenyl)isoxazolin-5(R, S)-ylacetyl]-L-2,3-diaminopropionic Acid TFA Salt
Part A. 3-(4-cyanophenyl)isoxazolin-5(R, S)-ylacetic acid.
To a solution of 4-cyanobenzaldoxime (see Ex 43, Part A) (312 g, 2.13 mol) in tetrahydrofuran (3000 ml) at room temperature was added vinyl acetic acid (552 g, 6.41 mol). The yellow solution was cooled in an ice bath and sodium hypochlorite solution (5200 ml) was added in a dropwise fashion over 2h. After stirring overnight at room temperature the reaction was quenched with a 5% citric acid solution and diluted with 200 ml ether. The layers were separated and the aqueous acidified to pH 4 using citric acid. The acid layer was washed twice with 200 ml ether, the ether layers combined and extracted with saturated sodium bicarbonate solution. After acidifying the basic layer with citric acid, the product was extracted into 400 ml ether. The organic phase was washed three times with 150 ml water, once with brine, dried (MgSO4) and concentrated to give 220 g of 3-(4-cyanophenyl)isoxazolin-5-ylacetic acid as a white solid. Recrystallization from 25% water/ethanol yielded 165 g of analytically pure material. Anal. Calcd for C12 H10 N2 O3 : C,62.61; H,4.38; N, 12.17. Found: C. 62.37; H 4.47; N, 11.71. 1 H NMR(300 MHz, CDCl3): δ 7.77-7.76 (d, 2H, J=1.8 Hz); 7.72-7.71 (d, 2H, J=1.8 Hz); 5.22-5.14 (m, 1H); 3.63-3.54 (dd, 1H, J=10.6 Hz, 16.8 Hz); 3.19-3.11 (dd, 1H, J=7.3Hz, 16.8 Hz); 3.00-2.93 (dd, 1H, J=6.2 Hz, 16.5 Hz); 2.79-2.72 (dd, 1H, J=7.3 Hz, 16.5 Hz). IR(KBr pellet): 3202, 2244, 1736, 1610, 1432, 1416, 1194, 1152, 928, 840, 562 cm-1.
Part B. Methyl N2 -Cbz-L-2,3-diaminopropionate HCl salt.
N2 -Cbz-L-2,3-diaminopropionic acid (10 mmol, 2.39 g) was dissolved in 20 mL methanol and 20 mL 4 N HCl in dioxane and the solution was stirred for 4 hours and then concentrated to give a solid. The solid was washed with ether several times to give 2.50 g (87%) product. NMR (DMSO-d6): δ 8.38 (b, 3H); 7.96 (d, 1H); 7.38 (m, 5H); 5.05 (s, 2H); 4.44 (m, 1H); 3.66 (s, 3H); 3.14 (m, 2H).
Part C. Methyl N2 -Cbz-N3 -[3-(4-cyanophenyl)isoxazolin-5(R, S)-ylacetyl]-L-2,3-diaminopropionate.
To a solution of 3-(4-cyanophenyl)isoxazolin-5(R, S)-ylacetic acid. (19 mmol, 4.37 g), methyl N2 -Cbz-L-2,3-diaminopropionate HCl salt (20 mmol, 5.76 g) and triethylamine (60 mmol, 8.36 mL) was added TBTU (20 mmol, 6.42 g) and the solution was stirred for 2 hours. Ethyl acetate was added and the solution was washed with dilute citric acid, brine, NaHCO3 and brine, dried (MgSO4), and concentrated. Crystallization from ethyl acetate/ether gave 6.85 g (78%) product. NMR (DMSO-d6): δ 8.16 (t, 1H); 7.92 (d, 2H); 7.82 (d, 2H); 7.68 (d, 1H); 7.36 (m, 5H); 5.04 (m, 3H); 4.20 (m, 1H); 3.64 (s, 3H); 3.50 (m, 2H); 3.26 (m, 2H); 2.50 (m, 2H).
Part D. Methyl N3 -[3-(4-amidinophenyl)isoxazolin-5(R, S)-ylacetyl]-L-2,3-diaminopropionate HCl salt.
HCl gas was bubbled into a solution of methyl N2 -Cbz-N3 -[3-(4-cyanophenyl)isoxazolin-5(R, S)-ylacetyl]-L-2,3-diaminopropionate (2.1 mmol, 1.0 g) for 1 hour and the solution was stirred overnight and concentrated. The residue was dissolved in 30 mL 2 M ammonia in methanol and the solution was stirred overnight. and concentrated to give 1.2 g crude product.
Part E. N3 -[3- (4-amidinophenyl)isoxazolin-5(R,S)-ylacetyl]-L-2,3-diaminopropionic acid TFA salt.
Methyl N3 -[3-(4-amidinophenyl)isoxazolin-5(R, S)-ylacetyl]-L-2,3-diaminopropionate HCl salt (200 mg) was saponified with 1 mL methanol and 1 mL 1 N NaOH for 1 hour and acidified with acetic acid. Purification on reversed phase HPLC gave 40 mg product. ESI (M+H)+ : Calcd 334.2; Found 334.2.
EXAMPLE 276 N2 -Cbz-N3 -[3-(4-amidinophenyl)isoxazolin-5(R, S)-ylacetyl]-L-2,3-diaminopropionic acid TFA salt
Part A. Methyl N2 -Cbz-N3 -[3-(4-amidinophenyl)isoxazolin-5(R, S)-ylacetyl]-L-2,3-diaminopropionate TFA salt.
To a solution of the compound of Ex. 275, part D (1.0 mmol, 385 mg) and sodium bicarbonate (5.0 mmol, 400 g) in 2 mL water, 2 mL acetonitrile and 1 mL DMF was added benzyl chloroformate (1 mmol, 143 μL) and the mixture was stirred for 2 hours at room temperature. The solution was filtered, acidified with TFA and purified on reversed phase HPLC to give 150 mg (25%) product. NMR (DMSO-d6): δ 9.40 (s, 2H); 9.20 (s, 2H); 8.18 (t, 1H); 7.86 (m, 4H); 7.68 (d, 1H); 7.35 (m, 5H); 5.02 (m, 3H); 4.20 (m, 1H); 3.64 (s, 3H); 3.52 (m, 2H); 3.26 (m, 2H); 2.50 (m, 2H).
Part B. N2 -Cbz-N3 -[3-(4-amidinophenyl)isoxazolin-5(R, S)-ylacetyl]-L-2,3-diaminopropionic acid TFA salt
Methyl N2 -Cbz-N3 -[3-(4-amidinophenyl)isoxazolin-5(R, S)-ylacetyl]-L-2,3-diaminopropionate TFA salt (0.12 mmol, 70 mg) was dissolved in 2 mL methanol and 1 mL 1 N NaOH and after 1 hour, the solution was acidified with acetic acid. Purification on reversed phase HPLC gave 50 mg (74%) product. ESI (M+H)+ : Calcd 468.2; Found 468.2.
EXAMPLE 278 N2 -n-butyloxycarbonyl-N3 -[3-(4-amidinophenyl)isoxazolin-5(R, S)-ylacetyl]-L-2,3-diaminopropionic acid TFA salt
Part A. Methyl N2 -n-butyloxycarbonyl-N3 -[3-(4-amidinophenyl)isoxazolin-5(R, S)-ylacetyl]-L-2,3-diaminopropionate TFA salt.
To a solution of the compound of Ex. 275, part E (1.0 mmol, 385 mg) and sodium bicarbonate (2.5 mmol, 200 mg) in 2 mL water, 2 mL acetonitrile and 1 mL DMF cooled in an ice bath was added n-butyl chloroformate (1 mmol, 127 μL). After stirring for 1 hour, the solution was acidified with acetic acid and purified on reversed phase HPLC to give 150 mg (27%) product. NMR (DMSO-d6): δ 9.40 (s, 2H); 9.20 (s, 2H); 8.16 (t, 1H); 7.86 (m, 4H); 7.47 (d, 1H); 5.02 (m, 1H); 4.16 (m, 1H); 3.94 (t, 2H); 3.62 (s, 3H); 3.50 (m, 2H); 3.26 (m, 2H); 2.50 (m, 2H); 1.52 (m, 2H); 1.32 (m, 2H); 0.88 (t, 3H). ESI (M+H)+ : Calcd 448.3; Found 448.3.
Part B. N2 -n-butyloxycarbonyl-N3 -[3-(4-amidinophenyl)isoxazolin-5(R, S)-ylacetyl]-(S)-2,3-diaminopropionic acid TFA salt.
Methyl N2-n-butyloxycarbonyl-N3-[3-(4-amidinophenyl)isoxazolin-5(R, S)-ylacetyl]-(S)-2,3-diaminopropionate TFA salt (0.107 mmol, 60 mg) was dissolved in 2 mL methanol and 2 mL 1 N NaOH and after 1 hour, the solution was acidified with acetic acid. Purification on reversed phase HPLC gave 53 mg (89%) product. ESI (M+H)+ : Calcd 434.3; Found 434.3.
EXAMPLE 278a Methyl N2 -n-butyloxycarbonyl-N3 -[3-(4-amidinophenyl)isoxazolin-5(R)-ylacetyl]-(S)-2,3-diaminopropionate Mesylate salt.
Methyl N2 -n-butyloxycarbonyl-N3 -[3-(4-amidinophenyl)isoxazolin-5(R)-ylacetyl]-(S)-2,3-diaminopropionate (500 mg, 1.03 mmol) was dissolved in 20 mL methanol and methanesulfonic acid (0.335 mL, 5 mmol) was added. The solution was allowed to stand at room temperature overnight and the solvent was removed by concentration. The residue was taken up in 20 mL methanol and the solution was allowed to stand at room temperature overnight. The solvent was removed by concentration and the residue was triturated with 8 mL 2-propanol. The solid product was isolated by filtration and dissolved in 12 mL 2-propanol by warming. After cooling to room temperature, crystalline solid formed. The mixture was allowed to stand in a refrigerator overnight. The crystal was filtered, washed with cold 2-propanol and dried. Yield 230 mg (41%). ES-MS (M+1): calcd 448.3; found 448.3. Analysis for C22 H33 N5 O9 S: calcd C 48.61, H 6.13, N 12.88; found C 48.38, H 5.91, N12.65.
EXAMPLE 278b N2 -n-butyloxycarbonyl-N3 -[3-(4-amidinophenyl)isoxazolin-5(R)-ylacetyl]-(S)-2,3-diaminopropionic acid TFA salt.
To a solution of methyl N2 -n-butyloxycarbonyl-N3 -[3-(4-amidinophenyl)isoxazolin-5(R)-ylacetyl]-(S)-2,3-diaminopropionate hydrochloride salt (600 mg, 1.24 mmol) in 20 mL MeOH and 20 mL water cooled in an ice bath was added 1 N LiOH (1.3 mL, 1.3 mmol) over 5 min and the solution was stirred at room temperature for 5 hours. The solvents were removed by concentration at 25° C. The residue was taken up in 3 mL water, 3 mL acetonitrile, and 0.2 mL TFA. Purification by reversed phase HPLC gave 610 mg (89%) product. ES-MS (M+1): calcd 434.3; found 434.3.
EXAMPLE 298 N2 -n-Butanesulfonyl-N3 -[3-(4-amidino-phenyl)isoxazolin-5(R,S)-ylacetyl]-(S)-2,3-diaminopropionic Acid TFA Salt
Prepared according to Example 490a. MS (ESI, e/z, relative intensity): 454 (M+H)+, (100%).
EXAMPLE 299 N2 -Phenylsulfonyl-N3 -[3-(4-amidinophenyl)isoxazolin-5(R,S)-ylacetyl]-(S)-2,3-diaminopropionic Acid TFA Salt
Prepared according to Example 490a. MS (ESI, e/z, relative intensity): 474 (M+H)+, (100%).
EXAMPLE 314A Methyl N2 -n-butyloxycarbonl-N3 -[3-(4-amidinophenyl)isoxazolin-5(S)-ylacetyl]-(S)-2,3-diaminopropionate TFA salt
Part A: Methyl N2 -Cbz-N3 -Boc-L-2,3-diaminopropionate.
To a solution of methyl N2 -Cbz-(S)-2,3-diaminopropionate HCl salt (16.3 mmol, 4.7 g) and ditert-butyl dicarbonate (16.3 mmol, 3.56 g) in 30 mL chloroform cooled in an ice bath was added triethylamine (34 mmol, 4.7 mL) and the solution was stirred in the ice bath for 1 hour and at room temperature for 3 hours and concentrated. The residue was taken up in ethyl acetate and the solution was washed with dilute citric acid, brine, NaHCO3 and brine, dried (MgSO4), and concentrated. Crystallization from ether/petroleum ether gave 5.2 g (92%) product. NMR (DMSO-d6): δ 7.60 (d, 1H); 7.35 (m, 5H); 6.88 (t, 1H); 5.02 (s, 2H); 4.14 (m, 1H); 3.60 (s, 3H); 3.28 (m, 2H); 1.37 (s, 9H).
Part B: Methyl N3 -Boc-(S)-2,3-diaminopropionate Formic acid salt.
A mixture of methyl N2 -Cbz-N3 -Boc-(S)-2,3-diaminopropionate. (14 mmo, 5.0 g), formic acid (42 mmol, 1.6 mL) and 10% Pd/C (500 mg) in 40 mL methanol was stirred at room temperature for 1 hour and filtered through a celite. The filtrate was concentrated and the residue was triturated with ether-petroleum ether to give 3.7 g (100%) solid product. NMR (DMSO-d6): δ8.20(s, 1H); 6.90 (t, 1H); 5.36 (b, 3H); 3.61 9s, 3H); 3.51 (t, 1H); 3.18 (t, 2H); 1.38 (s, 9H).
Part C: Methyl N2 -n-butyloxycarbonyl-N3 -Boc-(S)-2,3-diaminopropionate.
To a mixture of methyl N3 -Boc-(S)-2,3-diaminopropionate HCO2 H salt (14 mmol, 3.7 g) and NaHCO3 (40 mmol, 3.4 g) in 10 mL water and 10 mL THF cooled in an ice bath was added slowly butyl chloroformate (16 mmol, 2 mL) over 15 min. After stirring for 1 hour, ethyl acetate was added and the solution was washed with dilute citric acid, brine, NaHCO3 and brine, dried (MgSO4), and concentrated to give 4.4 g (100%) oily product. NMR (DMSO-d6): δ 7.37 (d, 1H); 6.84 (t, 1H); 4.10 (m, 1H); 3.96 (t, 2H); 3.60 (s, 3H); 3.26 (m, 2H); 1.52 (m, 2H); 1.38 (s, 9H); 1.36 (m, 2H); 0.88 (t, 3H).
Part D: Methyl N2 -butyloxycarbonyl-(S)-2,3-diaminopropionate TFA salt.
Methyl N2 -n-butyloxycarbonyl-N3 -Boc-(S)-2,3-diaminopropionate (13.9 mmol, 4.4 g) was dissolved in 25 mL methylene chloride and 35 mL TFA and after 1 hour, the solution was concentrated to give an oily product. Yield 4.8 g (100%). NMR (DMSO-d6): δ 8.02 (b, 3H); 7.68 (d, 2H); 4.38 (m, 1H); 3.99 (t, 2H); 3.68 (s, 3H); 3.22 (m, 1H); 3.06 (m, 1H); 1.55 (m, 2H); 1.34 (m, 2H); 0.89 (t, 3H).
Part E: Methyl-N2 -n-butyloxycarbonyl-N3 -[3-(4-cyanophenyl)isoxazolin-5(S)-ylacetyl]-(S)-2,3-diaminopropionate
To a solution of 3-(4-cyanophenyl)isoxazolin-5(S)-ylacetic acid (5.2 mmol, 1.2 g) [Chiral starting material was prepared from the racemic compound of Ex. 275, Part A by resolution on a 50 X 2 cm Chiralpak AD column using 0.1% TFA/EtOH at 10° C. to give S-isomer (faster eluting) and R-isomer (slower eluting). Alternately, the isomers were resolved by crystallization of the chinconidine salt of the 5-S isomer of the isoxazolines from acetone, leaving the 5(R),isomer in the mother liquor. The absolute stereochemistry of the crystalline salt was determined by X-ray crystallography to be the 5(S) isoxazoline.] and methyl N2 -butyloxycarbonyl-(S)-2,3-diaminopropionate TFA salt (6 mmol, 1.53 g) in 20 ml DMF cooled in an ice bath was added diisopropylethylamine (20 mmol, 3.5 mL) followed by BOP (5.5 mmol, 2.43 g). After stirring at room temperature for 3 hours, ethyl acetate was added and the solution was washed with 0.5 N HCl, brine, NaHCO3 and brine, dried (MgSO4), and concentrated to give 1.9 g (87%) product. NMR (DMSO-d6): δ 8.12 (t, 1H); 7.94 (d, 2H); 7.83 (d, 2H); 7.46 (d, 1H); 5.04 (m, 1H); 4.16 (m, 1H); 3.96 (t, 2H); 3.64 (s, 3H); 3.58 (dd, 1H); 3.40 (m, 2H); 3.20 (dd, 1H); 2.56 (dd, 1H); 2.43 (dd, 1H); 1.52 (m, 2H); 1.32 (m, 2H); 0.88 (t, 3H).
Part F: Methyl-N2 -n-butyloxycarbonyl-N3 [3-(4-amidinophenyl)isoxazolin-5(S)-ylacetyl]-(S)-2,3-diaminopropionate TFA salt.
To a solution of methyl-N2 -n-butyloxycarbonyl-N3 -[3-(4-cyanophenyl)isoxazolin-5(S)-ylacetyl]-(S)-2,3-diaminopropionate (4.4 mmol, 1.9 g) in 50 mL methanol was bubbled with HCl gas at 0° C. for 1 hour and the solution was stirred at room temperature for 5 hours and concentrated. The residue was taken up in 20 mL methanol and ammonium carbonate (11 mmol, 1.1 g) was added. The mixture was stirred at room temperature overnight and concentrated. The solid was dissolved in ethanol/water/TFA and purification on reversed phase HPLC gave 1.0 g (40%) product. ESI (M+H)+ : Calcd 448.3; Found 448.3.
EXAMPLE 314B Methyl-N2 -n-butyloxycarbonyl-N3 -[3-(4-amidinophenyl)isoxazolin-5(R)-ylacetyl]-(S)-2,3-diaminopropionate TFA salt
Part A: 3-(4-cyanophenyl)-5(R)-ylacetic acid
This material was resolved from 3-(4-cyanophenyl)isoxazolin-5(R,S)-ylacetic acid as described above in the proceudure for Example 314A, Part E.
Part B: Methyl-N2 -n-butyloxycarbonyl-N3 -[3-(4-cyanophenyl)isoxazolin-5(R)-ylacetyl]-(S)-2,3-diaminopropionate.
This material was synthesized from 3-(4-cyanophenyl)-5(R)-ylacetic acid (4.3 mmol, 1.0 g), Methyl N2 -butyloxycarbonyl-(S)-2,3-diaitinopropionate TFA salt (5 mmol, 1.27 g), BOP (4.5 mmol, 2 g) and diisopropylethylamine (16 mmol, 2.8 mL) using the same procedure as for XVI. Yield 1.75 g (95%). NMR (DMSO-d6): δ 8.12 (t, 1H); 7.94 (d, 2H); 7.83 (d, 2H); 7.46 (d, 1H); 5.04 (m, 1H); 4.16 (m, 1H); 3.96 (t, 2H); 3.64 (s, 3H); 3.58 (dd, 1H); 3.40 (m, 2H); 3.20 (dd, 1H); 2.56 (dd, 1H); 2.43 (dd, 1H); 1.52 (m, 2H); 1.32 (m, 2H); 0.88 (t, 3H).
Part C: Methyl-N2 -n-butyloxycarbonyl-N3 -[3-(4-amidinophenyl)isoxazolin-5(R)-ylacetyl]-(S)-2,3-diaminopropionate TFA salt
This compound was synthesized from Methyl-N2 -n-butyloxycarbonyl-N3 -[3-(4-cyanophenyl)isoxazolin-5(R)-ylacetyl]-(S)-2,3-diaminopropionate (4.0 mmol, 1.7 g) using the same procedure as for Example 314A, Part G. Yield 1.0 g (45%). ESI (M+H)+ : Calcd 448.3; Found 448.3.
EXAMPLE 317 N2 -(2-Phenylethylsulfonyl)-N3 -[3-(4-amidinophenyl)isoxazolin-5(R,S)-ylacetyl]-(S)-2,3-diaminopropionic Acid TFA Salt
Prepared according to Example 490a. MS (ESI, e/z, relative intensity): 502 (M+H)+, (100%).
EXAMPLE 344 Methyl 3(R)-{5(R,S)-N-[3-(4-Amidinophenyl)isoxazolin-5-ylacetyl]amino}heptanoate
Part A. (E)-Methyl 2-heptenoate
To a solution of diethyl methylphosphonoacetate (19 ml, 104 mmol) in dry THF (800 ml) at -4° C. was added 64 ml of n-BuLi (1.6 M in hexane, 102 mmol) dropwise over 45 min. The resulting solution was stirred 1 h at room temp. Valeraldehyle (10.0 ml, 94 mmol) was added and stirred 3.5 h at room temp. The reaction was quenched with 25 ml sat. NH4 Cl. Solvents were distilled at atmospheric pressure, and the resulting solids were taken up in EtOAc, extracted with water and brine, and dried with Na2 SO4. The solvents were again distilled at atmospheric pressure, and the resulting yellow liquid was distilled under house vacuum to yield 7.2 g clear liquid, boiling range under house vacuum 90-125° C.; HRMS, e/z Calc. for (M+H)+ : 143.1072. Found: 143.1070; IR(film) 1728, 1658 cm-1.
Part B. N-(1-(R)-1-Phenylethyl)benzamide
A solution of benzoyl chloride (22.5 mL, 0.19 mole) in dichloromethane (10 mL) was added dropwise over 1.5 h to a 0° C. solution of (R)-(+)-α-methylbenzylamine (25 mL, 0.19 mole), triethylamine (31 mL, 0.22 mole), and 4-DMAP (100 mg), in dichloromethane (1 L). After 1.75 h at 0° C. the mixture was concentrated in vacuo, then diluted with EtOAc. This mixture was extracted with water, 1 M HCl, water, and brine, then dried (MgSO4) and concentrated to yield 43.4 g of a colorless crystalline solid; mp 121.0-121.5° C.; IR(KBr) 3332, 1636 cm-1 ; [α]D 25 -2.30° (c=1.002, CH2 Cl2); Anal. Calc. for C15 H15 NO: C, 79.97; H, 6.71; N, 6.22. Found: C, 79.88; H, 6.65; N, 6.17.
Part C. N-(1-(R)-1-Phenylethyl)-N-benzylamine
BH3 /THF (1 M in THF, 220 mL, 220 mmol) was added dropwise over 1 h to a 0° C. solution of the above benzamide (20 g, 89 mmol) in dry THF (200 mL). The ice bath was removed, and the mixture was heated to reflux for 40 h. A TLC analysis indicated incomplete reaction, so more BH3 /THF (1 M in THF, 30 mL, 30 mmol) was added, and heating resumed for 22.5 h. After cooling, MeOH (250 mL) was added dropwise cautiously over 5 h. The resulting mixture was boiled for 2 h, then cooled and concentrated in vacuo. Reconcentration from MeOH (2×500 mL) and drying under high vacuum gave 19.3 g of an oil containing a small amount of a precipitate. This crude product was stirred with hot 2 M HCl (140 mL) to generate a clear solution, then slowly cooled to RT, and ultimately in an ice bath to yield a crystalline solid, as described by Simpkins (Tetrahedron 1990, 46(2), 523). The solid was collected by filtration and rinsed with a small amount of water. After air drying for 3 d, 16.35 g of the hydrochloride salt was obtained; mp 178.5-179.5° C.; [α]D 21 +18.9° (c=4.0, EtOH). The salt was converted to the free base by extraction with Et2 O and aq. KOH, then Kugelrohr distilled, oven temp. 120-140° C. (1.1 mm Hg) to give 12.5 g of an oil; [α]D 21 +61.2° (c=3.98, EtOH); Anal. Calc. for C15 H17 N: C, 85.26; H, 8.11; N, 6.63. Found: C, 84.93; H, 7.75; N, 6.58.
Part D. Methyl 3-(R)-[N-benzyl-N-(1-(R)-1-phenylethyl)amino]heptanoate
Following the asymmetric Michael addition method of Davies (Tetrahedron:Asymmetry 1991, 2(3), 183), n-butyllithium (1.6 M in hexanes, 4.4 mL, 7.0 mmol) was added dropwise over 3 min to a 0° C. solution of N-(1-(R)-1-phenylethyl)-N-benzylamine (1.5 g, 7.0 mmol) in dry THF (35 mL). After 30 min, the resulting dark pinkish-red solution was cooled to -78° C., and a solution of methyl 2-heptenoate (0.50 g, 3.5 mmol) in THF (10 mL) was added dropwise over 10 min. After 13 min, the cold reaction was quenched with saturated NH4 Cl (7 mL). After warming to RT, the mixture was extracted with Et2 O and brine, dried (MgSO4), and concentrated in vacuo. The product was purified by chromatography over silica gel, eluting with 0% to 50% EtOAc in hexane. The cleanest major product fractions (apart from a few mixed fractions) were concentrated in vacuo to give 0.91 g of a pale yellow oil which by NMR is a single diastereomer, with the newly generated asymmetric center assigned as 3(R) by analogy with the Davies reference above; 13 C NMR (300 MHz, CDCl3) δ 173.31, 143.40, 141.78, 128.40, 128.27, 128.11, 128.00, 126.91, 126.67, 57.90, 54.22, 51.32, 50.05, 36.83, 33.28, 29.32, 22.72, 19.40, 14.12; [α]D 25 +12.96° (c=0.602, MeOH).
Part E. Methyl 3-(R)-aminoheptanoate  acetic acid salt
Methyl 3-(R)-[N-benzyl-N-(1-(R)-1-phenylethyl)amino]heptanoate (0.70 g, 2.0 mmol), 20% Pd(OH)2 /C (0.35 g), cyclohexene (7 mL), glacial HOAc (0.12 mL, 2.1 mmol), and MeOH (14 mL) were heated at reflux under N2 for 20.5 h. After cooling, the catalyst was removed by filtration thru a Celite plug, rinsed with MeOH, and the solution concentrated in vacuo. Drying overnight under high vacuum yielded 0.43 g of a viscous oil; 13 C NMR (300 MHz, CDCl3) δ 177.64, 171.52, 51.97, 48.22, 37.24, 33.08, 27.50, 23.31, 22.29, 13.76; [α]D 25 -10.6° (c=0.602, MeOH).
Part F. Methyl 3(R)-[5(R,S)-N-[3-(4-cyanophenyl)isoxazolin-5-ylacetyl]amino}heptanoate
To a suspension of 3-(4-cyanophenyl)isoxazolin-5-ylacetic acid (300 mg, 1.3 mmol) in EtOAc (10 ml) was added methyl 3-(R)-aminoheptanoate acetic acid salt (287 mg, 1.3 mmol), TBTU (420 mg, 1.3 mmol), and Et3N (600 μl, 4.3 mmol). After stirring at room temp 2.5 h, the reaction mixture was extracted with 5% KHSO4, sat NaHCO3, and brine, then dried with Na2 SO4. Evaporation, followed by chromatography over silica gel in 50-100% EtOAc/hexanes yielded 245 mg colorless glass. MS (NH3 -DCI) Calc. for (M+H)+ : 372, (M+NH4)+ : 389. Found: 372, 389.
Part G. Methyl 3(R)-{5(R,S)-N-[3-(4-Amidinophenyl)isoxazolin-5-ylacetyl]amino}heptanoate
To a solution of methyl 3(R)-{5(R,S)-N-[3-(4-cyanophenyl)isoxazolin-5-ylacetyl]amino}heptanoate (179 mg, 0.48 mmol) in 15 ml dry MeOH at 0° C., was added a stream of HCl gas generated from dropping two 20 ml portions of H2 SO4 into solid NaCl over 35 min. After stirring 20 h at room temp, the solvent was removed with a rapid stream of N2. Et2 O was added and removed with a rapid stream of N2. The resulting gummy oil was taken up in 15 ml dry MeOH, to which was added (NH4)2 CO3 (1.1 g, 11.4 mmol). After stirring 19.5 h at room temp, the solvent was removed with a rapid stream of N2, and the resulting white solid was purified by chromatography over silica gel, eluting with 0-20% MeOH/CHCl3. Purified product was taken up in 5% MeOH/CHCl3 and filtered. Concentration of the filtrate yielded 100 mg white solid. IR(KBr) 3600-2800, 1734, 1676, 1640 cm-1 ; HRMS, e/z Calc. for (M+H)+ : 389.2189. Found: 389.2192.
EXAMPLE 348 Ethyl 3(R)-{5(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-ylacetyl]amino}-5-methylhexanoate  trifluoroacetic Acid Salt
Part A. (E)-Ethyl 5-methyl-2-hexenoate
Prepared in analogous fashion to rethyl 2-heptenoate, using triethyl phosphonoacetate, stirring 17 h at room temp upon addition of isovaleraldehyde. Distillation under house vacuum yielded 72% clear oil, boiling range under house vacuum 80-130° C.; IR(film) 1724, 1656 cm-1.
Part B. Ethyl 3-(R)-[N-benzyl-N-(1-(R)-1-phenylethyl)amino]-5-methylhexanoate
Prepared in analogous fashion via the asymmetric Michael addition of Ex. 344, part D above. Yield a viscous pale yellow oil (65%); 13 C NMR (300 MHz, CDCl3) δ 172.83, 143.56, 142.17, 128.27, 128.21, 128.15, 128.03, 126.96, 126.60, 60.10, 58.56, 52.43, 50.09, 3.23, 36.72, 24.76, 23.48, 22.13, 20.20, 14.21; [α]D 25 +5.12° (c=0.606, EtOH).
Part C. Ethyl 3-(R)-amino-5-methylhexanoate  acetic acid salt
Prepared as previously described except EtOH was used as solvent. Yield a waxy solid (94%); mp 57-61° C.; HRMS, e/z Calc. for (M+H)+ : 174.1494. Found: 174.1485.
Part D. Ethyl 3-(R)-amino-5-methylhexanoate  hydrochloric acid salt
The above acetic acid salt (1.1 g, 4.7 mmol) was stirred 4 min in 4 M HCl/dioxane (5.0 ml). The resulting solution was triturated with Et2 O, cooled, and the clear liquid decanted, leaving an orange oil which solidified to 960 mg waxy solid on high vacuum; 1 H NMR (300 MHz, CDCl3) ∂ 8.49 (br, 3H), 4.20 (q, J=7.3, 2H), 3.70-3.65 (m, 1H), 2.86-2.80 (m, 2H), 1.83-1.80 (m, 2H), 1.58-1.54 (m, 1H), 1.30-1.26 (t, J=7.3, 3H), 0.99-0.91 (m, 6H).
Part E. Ethyl 3(R)-{5(R,S)-N-[3-(4-(N-t-butoxycarbonylamidino)phenyl)isoxazolin-5-ylacetyl]amino}-5-methylhexanoate
To a suspension of 3-(4-(N-t-butoxycarbonylamidino)phenyl]isoxazolin-5-ylacetic acid (78 mg, 0.22 mmol) in EtOAc (5 ml) was added ethyl 3-(R)-amino-5-methylhexanoate hydrochloride salt (47 mg, 0.22 mmol), TBTU (72 mg, 0.22 mmol), and Et3 N (100 μl, 0.72 mmol). After stirring 6 h at room temp, the reaction mixture was extracted with pH 4 buffer (potassium hydrogen phthalate), sat NaHCO3, and brine, then dried with Na2 SO4. Evaporation, followed by chromatography over silica gel in 100% EtOAc yielded 33 mg colorless glass; 1 H NMR (300 MHz, CDCl3) ∂ 7.90 (d, J=8.4, 2H), 7.70 (dd, J=8.5, J'=1.9, 2H), 6.32-6.28 (m, 1H), 5.13-5.11 (m, 1H), 4.34-4.33 (m, 1H), 4.17-4.09 (m, 2H), 3.56-3.47 (m, 1H), 3.25-3.17 (m, 1H), 2.71-2.46 (m, 4H), 1.66-1.47 (m, 2H), 1.56 (s, 9H), 1.31-1.23 (m, 4H), 0.92 (dd, J=6.6, J'=1.8, 3H), 0.84 (d, J=6.6, 3H).
Part F. Ethyl 3(R)-{5(R,S) -N-[3-(4-amidinophenyl)isoxazolin-5-ylacetyl]amino}-5-methyl hexanoate  trifluoroacetic acid salt
The product from Part E above (29 mg, 0.058 mmol) was dissolved in DCM (300 μl), to which was added TFA (100 μl). The resulting solution was stirred at room temp under a CaSO4 drying tube for 3.5 h, and triturated with Et2 O. 24 mg white solid were collected by filtration; 1 H NMR (300 MHz, CDCl3) ∂ 9.4 (br, 1H), 9.0 (br, 1H), 7.8 (s, 4H), 5.0 (m, 1H), 4.2 (m, 1H), 4.0 (q, 2H), 3.6 (m, 1H), 3.3 (m, 2H), 2.4 (m, 3H), 1.6 (m, 1H), 1.4 (m, 1H), 1.2 (m, 4H), 0.8 (m, 6H); HRMS, e/z Calc. for (M+H)+ : 403.2345. Found: 403.2363.
EXAMPLE 350 Methyl 3(R,S)-{5(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-ylacetyl]amino}-4-(phenylthio)butanoate  hydrochloric acid salt;
Part A. Methyl phenylthioacetoacetate
To a solution of thiophenol (5.00 ml, 48.6 mmol) in DMF (20 ml), K2 CO3 (10.09 g, 73 mmol) and methyl chloroacetoacetate (5.93 ml, 48.6 mmol) were added. The reaction mixture was stirred 6 h at 50° C., diluted with EtOAc, and extracted with saturated Na2 SO4, water, and brine, then dried (Na2 SO4) and concentrated. The resulting oil was chromatographed with 20% EtOAc in Hexane to yield 9.40 g yellow oil; MS (CH4-DCI) Calc. for (M+H)+ : 224. Found: 224; IR(KBr) 2954, 1656, 1438, 626 cm-1.
Part B. Methyl-3(R,S)-amino-4-penylthiobutanoate
To a solution of methyl phenylthioacetoacetate (1.00 g, 4.5 mmol) in MeOH (20 ml), ammonium formate (4.26 g, 6.75 mmol) and sodium cyanoborohydride (0.42 g, 6.7 mmol) were added. The reaction mixture was stirred at room temperature for 18 h, then diluted with EtOAc and partitioned into 1 M HCl. The aqueous layer was then basified to pH=8.0 with NaOH. The desired product was extracted out with EtOAc, washed with water and brine, dried over Na2 SO4 and concentrated to yield 0.61 g yellow oil; MS (NH3-CI/DDIP) Calc. for (M+H)+ : 226. Found: 226; 1 H NMR (300 MHz, CDCl3) δ 7.39 (d, J=7, 2H), 7.32-7.26 (m, 3H), 7.22 (d, J=10, 1H), 3.74 (s, 3H), 3.39-3.31 (m, 1H), 3.13-3.07 (dd, J=13, J'=9, 1H), 2.91-2.83 (dd, J=12, J'=6, 1H), 2.65-2.58 (dd, J=12, J'=6, 1H), 2.46-2.38 (dd, J=16, J'=8, 1H).
Part C. Methyl-3(R,S)-{5(R,S)-N-[3-(4-cyanophenyl)isoxazolin-5-ylacetyl]amino}-4-(phenylthio)butanoate
To a suspension of 3-(4-cyanophenyl)isoxazolin-5-ylacetic acid (0.50 g, 2 mmol) in EtOAc (10 ml), methyl-3(R,S)amino-4-(phenylthio)butanoate (0.51 g, 2 mmol), TBTU (0.71 g, 2 mmol), and Et3 N (1.24 ml, 8.9 mmol) were added. The reaction mixture was stirred 2 h at room temperature, diluted with EtOAc, washed with 5% citric acid, saturated NaHCO3, and brine, dried over Na2 SO4, concentrated, and the resulting oil was chromatographed over silica gel in 100% EtOAc to yield 0.61 g of a yellow glass: MS (NH3 -CI/DDIP) Calc. for (M+H)+ : 438.1. Found: 438.1; Anal. Calc. for C32 H23 N3 O4 S1 : C, 63.31; H, 5.30; N, 9.60; S, 7.33. Found: C, 62.99; H, 5.22; N, 9.53; S, 7.30.
Part D. Methyl 3(R,S)-{5(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-ylacetyl]amino}-4-(phenylthio)butanoate  hydrochloric acid salt
The product from Part C above (0.30 g,0.68 mmol) was dissolved in dry MeOH (20 ml) at 0° C. To the resulting solution, HCl gas was bubbled in from a generator as described in Example 344, Part G, over a period of 2 h. The generator was removed and the reaction mixture stirred at 0° C. for 18 h, then concentrated and triturated with CHCl3. The resulting precipitate was collected by filtration and redissolved in dry MeOH (20 ml). To this solution, ammonium carbonate (0.99 g, 10 mmol) was added and the mixture stirred at room temperature for 18 h. The solution was concentrated and recrystallized from DCM/MeOH to yield 0.14 g white solid; HRMS, e/z Calc. for (M+H)+ : 455.1753. Found: 455.175; 1 H NMR (300 MHz, d6 -DMSO) δ 9.44 (br s, 1H), 9.18 (br s, 1H), 8.22 (d, J=10, 1H), 7.86 (m, 4H), 7.41-7.25 (m, 4H), 7.2 (m, 1H), 5.03 (m, 1H), 4.2 (m, 1H), 3.59 (s, 3H), 3.29-3.05 (m, 4H), 2.8-2.39 (m, 4H).
EXAMPLE 359 Methyl 3(R,S)-{5(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-ylacetyl]amino}-4-(phenylsulfonamido)butanoate  Trifluoroacetic Acid Salt;
Part A. Methyl 3-(R,S)-hydroxy-4-aminobutanoate  hydrochloric acid salt
Chlorotrimethylsilane (100 mL, 0.79 mol) was added dropwise over 1.5 h to a stirred 0° C. suspension of 4-amino-3-(R,S)-hydroxybutyric acid (25 g, 0.21 mol) in MeOH (1 L). The resulting clear solution was allowed to slowly warm to room temperature overnight. The solvent was evaporated in vacuo, and the resulting residue was reconcentrated from more MeOH (2×500 mL). Drying under high vacuum produced 37 g of a-viscous oil; 13 C NMR (300 MHz, d6 -DMSO) δ 171.42, 90.14, 64.67, 51.89, 44.39; Anal. Calc. for C5 Hl6 ClNO3 : C, 35.41; H, 7.13; N, 8.26; Cl, 20.90. Found: C, 35.18; H, 7.09; N, 8.18; Cl, 20.77.
Part B. Methyl 3-(R,S)-hydroxy-4-(phenylsulfonamido)butanoate
A solution of benzenesulfonyl chloride (7.5 mL, 59 mmol) in dichloromethane (10 mL) was added dropwise over 55 min to a 0° C. solution of the Part A amine salt (10 g, 50 mmol), and Et3 N (17 mL, 120 mol) in dichloromethane (110 mL). The mixture was allowed to slowly warm to room temperature, and stirring was continued over the weekend. After solvent removal in vacuo, the mixture was diluted with EtOAc and extracted with H2 O, 0.1 M HCl, and brine. Drying (MgSO4) and solvent removal in vacuo yielded 14.6 g of a viscous oil; 13 C NMR (300 MHz, CDCl3) δ 172.67, 139.79, 132.78, 129.22, 127.02, 66.77, 52.01, 47.72, 38.31; Anal. Calc. for C11 H15 NO5 S: C, 48.34; H, 5.53; N, 5.13; S, 11.73. Found: C, 48.44; H, 5.61; N, 4.90; S, 11.34.
Part C. Methyl 3-oxo-4-(phenylsulfonamido)butanoate
The Part B alcohol (2.8 g, 10 mmol) was oxidized with Jones reagent under standard conditions. The ketone was purified by chromatography on silica gel, eluting with 0% to 100% EtOAc in hexane, to yield 1.11 g of a waxy solid; mp 94.5-95.5° C.; 13 C NMR (300 MHz, CDCl3) δ 197.08, 166.80, 139.17, 133.08, 129.29, 127.17, 52.71, 51.91, 46.15; Anal. Calc. for C11 H13 NO5 S: C, 48.70; H, 4.83; N, 5.16; S, 11.82. Found: C, 48.77; H, 4.69; N, 5.08; S, 11.88.
Part D. Methyl 3-(R,S)-3-amino-4-(phenylsulfonamido)butanoate
To a room temperature solution of the Part C ketone (0.71 g, 2.6 mmol) in MeOH (7 mL) and THF (3 mL) was added ammonium formate (2.5 g, 39 mmol) and sodium cyanoborohydride (0.25 g, 3.9 mmol). After 45.5 h, solvent was evaporated, and the residue was diluted with EtOAc (70 mL). This solution was extracted with 1.0 M NaOH, H2 O, and brine. After concentration, the product was purified by chromatography on silica gel, eluting with 0% to 100% EtOAc in hexane, then 1% to 20% MeOH in EtOAc to yield 0.16 g of a viscous oil, which eventually solidified; 1 H NMR (300 MHz, CDCl3) ∂ 9.79 (br, 2H), 7.84 (d, 2H, J=8 Hz), 7.81 (br, 1H), 7.68-7.53 (m, 3H), 4.05-3.92 (m, 1H), 3.75 (s, 3H), 3.33-3.17 (m, 2H), 2.89-2.72 (m, 2H); HRMS, e/z Calc. for (M+H)+ : 273.0909. Found: 273.0916.
Part E. Methyl 3-(R,S)-{5(R,S)-N-[3-(4-(N-t-butoxycarbonylamidino)phenyl)isoxazolin-5-ylacetyl]amino}-4-(phenylsulfonamido)butanoate
This compound was prepared analogous to Example 348, Part E, stirring 24 h in 5 ml EtOAc and 1 ml DMF. Chromatography in 5% MeOH/CHCl3 yielded 80% of an orange solid; IR(KBr) 3296, 2338, 1736, 1660, 1618 cm-1 ; HRMS, e/z Calc. for (M+H)+ : 602.2285. Found: 602.2270.
Part F. Methyl 3(R,S)-{5(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-ylacetyl]amino}-4-(phenylsulfonamido)butanoae  trifluoroacetic acid salt
The product from Part E was deprotected analogously to Example 348, Part F, yielding 86% pink solid; IR(KBr) 3312, 3104, 1734, 1670; HRMS, e/z Calc. for (M+H)+ : 502.1760. Found: 502.1761. The more active diastereomer (based on PRP assay) was isolated from the above mixture by SFC HPLC, Chiralpak AD--2×25 cm, eluted with 0.1% TFA/25% MeOH/75% CO2. Under these conditions, the more active diastereomer eluted last.
EXAMPLE 362 Methyl 3(R,S)-{5(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-ylacetyl]amino}-4-(n-butylsulfonamido)butanoate  trifluoroacetic acid salt;
Part A. Methyl 3-(R,S)-hydroxy-4-(n-butylsulfonamido)butanoate
This compound was prepared entirely analogously to Ex.359, Part B, using n-butylsulfonylchloride instead. A colorless, waxy solid of excellent purity was obtained in 65% yield without purification; mp 46-50° C.; 13 C NMR (300 MHz, CDCl3) δ 172.64, 67.29, 52.56, 51.99, 47.83, 38.40, 25.57, 21.52, 13.55; Anal. Calc. for C9 H19 NO5 S: C, 42.67; H, 7.56; N, 5.53; S, 12.66. Found: C, 42.69; H, 7.59; N, 5.36; S, 12.78.
Part B. Methyl 3-oxo-4-(n-butylsulfonamido)butanoate
The immediately preceeding alcohol was oxidized as described for Example 359, Part C, to give a 57% yield of a colorless solid; mp 53-55° C.; Anal. Calc. for C9 H17 NO5 S: C, 43.02; H. 6.82; N, 5.57; S, 12.76. Found: C, 42.68; H, 7.03; N, 5.74; S, 13.06.
Part C. Methyl 3(R,S)-3-amino-4-(n-butylsulfonamido)butanoate
This compound was prepared analogous to Example 350, Part B, using the product from Part B above (1.20 g, 4.8 mmol) yielding 0.26 g yellow oil; 1H NMR (300 MHz, CDCl3) δ 3.70 (s, 3H), 3.38 (m, 1H), 3.24-3.13 (m, 1H), 3.02 (m, 4H), 2.58-2.52 (dd, J=16, J'=11, 1H), 1.79 (m, 2H), 1.24 (m, 2H), 0.95 (t, 3H); MS (NH4-DCI) Calc. for (M+H)+ : 271. Found: 271.
Part D. Methyl-3(R,S)-{5(R,S)-N-[3-(4-(N-t-butoxycarbonylamidine)phenyl)isoxazolin-5-ylacetyl]amino}-4-(n-butylsulfonylamidc)butanoate
To a solution 3-[4-(N-t-butoxycarbonylamidine)phenyl]isoxazolin-5-ylacetic acid (0.24 g, 0.83 mmol) in DMF (20 ml), the product from Part C above (0.29 gr, 0.83 mmol), TBTU (0.27 g, 0.83 mmol), and Et3 N (0.46 ml, 3.3 mmol) was added. After stirring 4 h at room temperature, the reaction mixture was diluted with EtOAc, extracted with pH 4 buffer (potassium hydrogen phthalate), saturated NaHCO3, brine, then dried (NaSO4). Concentration, followed by chromatography over silica gel in 100% EtOAc, yielded 1.17 g of a white foam; MS (NH3-DCI) Calc. for (M+H)+ : 582.3. Found: 582; IR(KBr) 3312, 2338, 1620, 1144 cm-1.
Part E. Methyl 3(R,S)-{5(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-ylacetyl]amino}-4-(n-butylsulfonylamido)butanoate  trifluoroacetic acid
To a solution of the product from Part D above (0.22 g, 0.37 mmol) in DCM (10 ml), trifluoroacetic acid (2.2 ml) was added. The reaction mixture was stirred 2 h at room temperature, triturated with Et2 O, and the resulting precipitate was chromatographed over silica gel in 20% MeOH in CHCl3 to yield 0.20 g white solid; HRMS, e/z Calc. for (M+H)+ : 482.2073. Found: 482.2090; mp=178-184° C.
EXAMPLE 365 Methyl {5(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-ylacetyl]amino}-4-(methoxycarbonyl)butanoate  trifluoroacetic Acid Salt
Part A. Dimethyl 3-aminoglutarate  hydrochloric acid salt
This product was prepared similarly to Example 359, Part A, from β-glutamic acid to yield the diester as a colorless gum in quantitative yield; HRMS, e/z Calc. for (M+H)+ : 176.0923. Found: 176.0933.
Part B. Methyl {5(R,S)-N-[3-(4-(N-t-butoxycarbonylamidino)phenyl)isoxazolin-5-ylacetyl]amino}-4-(methoxycarbonyl)butanoate
Prepared analogous to Example 359, Part E, to yield 32% of a white solid; IR(KBr) 3306, 2338, 1738, 1656, 1620 cm-1 ; HRMS, e/z Calc. for (M+H)+ : 505.2298. Found: 505.2283.
Part C. Methyl {5(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-ylacetyl]amino}-4-(methoxycarbonyl)butanoate  trifluoroacetic acid salt
Prepared analogous to Example 348, Part F, yielding 83% white solid; IR(KBr) 3316, 3102, 2340, 1736, 1670 cm-1 ; HRMS, e/z Calc. for (M+H)+ : 405.1774. Found: 405.1775.
EXAMPLE 368 Methyl 3(R,S)-{5(RS)-N-[3-(4-amidinophenyl)isoxazolin-5-ylacetyl]amino}-4-(methoxycarbonyl)-pentanoate  trifluoroacetic Acid Salt
Part A. Dimethyl 3-(R,S)-aminoadipate  hydrochloric acid salt
This product was prepared as in Example 359, Part A, from β-aminoadipic acid to yield a colorless gum in quantitative yield; HRMS, e/z Calc. for (M+H)+ : 190.1079. Found: 190.1080.
Part B. Methyl-3(R,S)-{5(R,S)-N-[3-(4-(N-t-butoxycarhonylamidine)phenyl)isoxzalin-5-ylacetyl]amino}-4-(methoxycarbonyl)pentanoate
This product was prepared similarly as in Example 362, Part D, using the product from Part B above (0.70 g, 3.1 mmol) instead to yield 1.17 g of a white foam; HRMS, e/z Calc. for (M+H)+ : 519.2454. Found: 519.2459; Anal. Calc. for C25 H34 N4 O8 : C, 57.90; H, 6.61; N,10.80. Found: C, 57.73; H, 6.51; N, 10.86.
Part C. Methyl-3(R,S)-{5(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-ylacetyl]amine}-4-(methoxyacarbonyl)pentanoate  trifluoroacetic acid salt
This product was prepared as in Example 362, Part E, using the product from Part C above (1.00 g, 1.9 mmol) to yield 0.9 g white solid; HRMS, e/z Calc. for (M+H)+ : 419.1930. Found: 419.1921; mp=214-215° C. (decomposes).
EXAMPLE 375 Preparation of 2-(R,S)-2-Carboxymethyl-1-{5-(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-yl acetyl]}piperidine
Part A. Preparation of 2-(Methoxy-2-oxoethyl)piperidine
Pyridylacetic acid hydrochloride (10.00 g, 57.6 mmol) and platinum(IV) oxide (1.00 g, 4.4 mmol) were shaken in a mixture of 75 ml acetic acid, 75 ml methanol, and 10 ml conc. HCl on Parr under 60 psi hydrogen at room temperature overnight. The mixture was then filtered through Celite, and the filtrate evaporated under reduced pressure to yield 8.42 g (75.9%) of the title compound as an off-white solid. MS (NH3 -CI/DDIP): m/e 158 (M+H)+. 1 H NMR (300 MHz, CDCl3): δ 1.50-1.96 (m, 6H); 2.80 (m, 2H); 3.20-3.60 (m, 3H); 3.76 (s, 3H). 13 C NMR (60 MHz, d6 -DMSO): δ 21.94; 28.05; 37.46; 40.49; 44.12; 57.33; 52.74; 170.39.
Part B. Preparation of 2-(R,S)-2-(Methoxy-2-oxoethyl)-1-{5-(R,S)-N-[3-(4-cyanophenyl)isoxazolin-5-yl acetyl]}piperidine
To 2.00 g (8.69 mmol) of 3-(4-cyanophenyl)-isoxazolin-5-yl acetic acid in 100 ml anhydrous DMF was added 1.36 g (8.69 mmol) of 2-(methoxy-2-oxoethyl)piperidine, 2.80 g (8.69 mmol) of TBTU, and 6.05 ml (34.7 mmol) of diisopropylethylamine. After stirring for 6 hrs, the reaction mixture was diluted with ethyl acetate and washed with 5% aqueous citric acid solution, water, 5% aqueous NaHCO3 solution, and saturated NaCl solution. The organic layer was dried over Na2 SO4 and filtered. The filtrate was evaporated under reduced pressure to give the crude product as a yellow foam. Purification by flash column chromatography on silica gel using 25-75% ethyl acetate in hexane yielded 1.54 g (48%) of the title compound as a yellow foam. One diastereomer (racemic) was isolated from the mixture. MS (NH3 -CI/DDIP): m/e 370 (M+H)+. 1 H NMR (300 MHz, CDCl3): δ 1.42-1.76 (m, 6H); 2.60 (m, 2H); 2.77-3.01 (m, 3H); 3.05-3.26 (m, 2H); 3.56-3.70 (m, 4H); 4.50 (m, 1H); 5.20 (m, 1H); 7.69 (d, J=8.4 Hz, 2H); 7.77 (d, J=8.4 Hz, 2H).
Part C. Preparation of 2-(Methoxy-2-oxoethyl)-1-{N- [3-(4-amidinophenyl)isoxazolin-5-yl acetyl]}piperidine, (racemic diastereomer A)
HCl gas was bubbled for 2 hrs through a solution of 1.02 g (2.80 mmol) of the product of part B above in 30 ml of anhydrous MeOH cooled in an ice bath. The reaction flask was then sealed with Teflon tape and warmed to room temperature while stirring overnight. MeOH was evaporated under reduced pressure and then under vacuum to give the intermediate imidate as a yellow foam. MS (ESI): m/e 402 (M+H)+. It was then stirred with 8.07 g (84.0 mmol) of (NH4)2 CO3 in 30 ml anhydrous EtOH overnight in a sealed reaction flask. After filtering, the filtrate was evaporated under reduced pressure to give the crude product as a yellow foam, which was then purified by flash column chromatography using 5-17% MeOH in CH2 Cl2 to give 0.29 g (26.8%) of the title compound as a yellow solid. MS (ESI): m/e 387 (M+H)+. 1 H NMR (300 MHz, d6 -DMSO): δ 1.57-1.67 (br., 6H); 2.46-2.90 (m, 5H); 3.16 (m, 2H); 3.53-3.64 (m, 4H); 4.36 (br. m, 1H); 5.07 (br. m, 1H); 7.89 (m, 4H); 9.38 (br. s, 3H).
Part D. Preparation of 2-Carboxymethyl-1-{N-[3-(4-amidinophenyl)isoxazolin-5-yl acetyl]}piperidine, (Racemic Isomer A)
To a solution of 0.08 g (0.2 mmol) of the product isolated in Part C above in 5 ml anhydrous THF at ambient temperature was added 0.5 ml (0.5 mmol) of 1.0 M solution of NaOTMS in THF. After stirring overnight, solvent was evaporated under reduced-pressure to give a yellow solid, which was recrystallized from MeOH and Et2 O to give 0.05 g (64.9%) of the title compound as a yellow powder. MS (ESI): m/e 373 (M+H)+. 1 H NMR (300 MHz, CD3 OD): δ 1.68 (br., 6H); 2.56 (m, 2H); 2.72 (m, 3H); 2.94 (m, 2H); 3.57 (m, 4H); 4.46 (br., 1H); 5.18 (br., 1H); 7.84 (m, 4H).
EXAMPLE 377 Preparation of 2-(R,S)-2-Carboxymethyl-1-{5-(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-yl acetyl]}azepine
Part A. Preparation of 2-(R,S)-2-(Ethoxy-2-oxoethyl)-1-{5-(R,S)-N-[3-(4-cyanophenyl)isoxazolin-5-yl acetyl]}azepine
From 0.50 g (2.17 mmol) of 3-(4-cyanophenyl)isoxazolin-5-yl acetic acid, using 0.40 g (2.17 mmol) of 2-(ethoxy-2-oxoethyl)azepine, 0.70 g (2.17 mmol) TBTU, and 1.51 ml (8.70 mmol) diisopropylethylamine, 0.73 g (84.6 %) of the title compound was obtained following the procedure of Example 375, Part B. MS (NH3 -CI/DDIP): m/e 398 (M+H)+. 1 H NMR (300 MHz, CDCl3): δ 1.26 (m, 11H); 1.83 (br., 2H); 2.05 (m, 1H); 2.18-2.65 (m, 2H); 2.76-2.85 (m, 1H); 3.04 (m, 2H); 3.62 (s, 1H); 4.08 (m, 2H); 5.22 (m, 1H); 7.68 (d, J=8.4 Hz, 2H); 7.78 (d, J=8.4 Hz, 2H).
Part B. Preparation of 2-(R,S)-2-(Ethoxy-2-oxoethyl)-1-{5-(R,S) -N-[3-(4-amidinophenyl)isoxazolin-5-yl acetyl]}azepine
From 0.73 g (1.84 mmol) of 2-(R,S)-2-(ethoxy-2-oxoethyl)-1-{5-(R,S)-N-[3-(4-cyanophenyl)isoxazolin-5-yl acetyl]}azepine, using EtOH as the solvent, 0.42 g (61.6%) of the title compound was obtained following the procedure of Example 375, Part C. MS (NH3-CI/DDIP): m/e 415(M+H)+. 1 H NMR (300 MHz, d6 -DMSO): δ 1.18 (m, 3H); 1.38 (m, 2H); 1.70 (m, 4H); 2.08 (br., 2H); 2.66 (m, 2H); 3.02-3.26 (m, 2H); 3.60 (br. m, 2H); 4.05 (m, 2H); 4.58 (,m, 1H); 5.10 (m, 1H); 7.90 (m, 4H); 9.38 (br. s, 3H).
Part C. Preparation of 2-(R,S)-2-Carboxymethyl-1-{5-(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-yl acetyl]}azepine
From 0.16 g (0.35 mmol) of 2-(R,S)-2-(ethoxy-2-oxoethyl)-1-{5-(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-yl acetyl]}azepine and using 0.89 ml (0.89 mmol) of 1.0 M solution of NaOTMS in THF, 0.12 g (82.9%) of the title compound was obtained following the procedure of Example 375, Part D. MS (NH3 -DCI): m/e 387 (M+H)+.
EXAMPLE 400 Preparation of 3-(R,S)-(Methoxy-2-oxoethyl)-4-{5-(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-yl acetyl]}piperazin-2-one
Part A. Preparation of 3-(R,S)-(Ethoxy-2-oxoethyl)-4-{5-(R,S)-N-[3-(4-cyanophenyl)isoxazolin-5-yl acetyl]}piperazin-2-one
From 1.00 g (4.34 mmol) of 3-(4-cyanophenyl)isoxazolin-5-yl acetic acid, using 0.81 g (4.34 mmol) of ethyl 2-piperazin-3-one acetate, 1.39 g (4.34 nmol) TBTU, and 3.02 ml (17.40 mmol) diisopropylethylamine, 1.08 g (62.4%) of the title compound was obtained following the procedure of Example 375, Part B. MS (NH3 -CI/DDIP): m/e 399 (M+H)+. 1 H NMR (300 MHz, CDCl3): δ 1.26 (m, 3H); 2.71-3.65 (br., 9H); 3.87 (br. m, 1H); 4.16 (m, 2H); 5.01 & 5.09 (two t, J=5.0, 5.1 Hz, 1H); 5.20 (m, 1H); 7.00 & 7.12 (two br., 1H); 7.77 (m, 4H).
Part B. Preparation of 3-(R,S)-(Methoxy-2-oxoethyl)-4-{5-(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-yl acetyl]}piperazin-2-one
From 1.08 g (2.71 mmol) of 3-(R,S)-(ethoxy-2-oxoethyl)-4-{5-(R,S)-N-[3-(4-cyanophenyl)isoxazolin-5-yl acetyl]}piperazin-2-one, 0.30 g (27.6%) of the title compound was obtained, following the procedure of Example 375, Part C. MS (ESI): m/e 402 (M+H)+. 1 H NMR (300 MHz, d6 -DMSO): δ 2.70-3.67 (m, 12H); 3.91 (br., 1H); 4.87 & 4.64 (two m, 1H); 5.06 (m., 1H); 7.88 (m, 4H); 8.16 (br., 1H); 9.40 (br. s, 3H).
EXAMPLE 434 Preparation of (S)-N.sup.α -[3-(4-Amidinoehenyl)-isoxazolin-5-(R,S) -ylacetyl]-α-aspart-N-(2-phenylethyl)amide, trifluoroacetic Acid Salt
Part A. Preparation of (S)-N.sup.α -(Benzyloxycarbonyl)-β-(O-t-butyl)-α-aspart-N-(2-phenylethyl)amide
To a solution of (S)-N-(Benzyloxycarbonyl)-β-(O-t-butyl)-aspartic acid (BACHEM-Bioscience Inc) (3.20 g, 9.9 mmol) in DCM (25 mL), was added phenethylamine (1.34 g, 11.1 mmol); followed by DEC (2.10 g, 10.9 nmol). The reaction mixture was stirred overnight at room temperature, affording a pale yellow solution. This solution was washed with water, 1M HCl, 5% NaHCO3 and sat. NaCl, dried over anhydrous MgSO4, filtered, and concentrated in vacuo to give 4.28 g (100%) of amide, which was of sufficient purity to be carried on to the next step; 1 H NMR (300 MHz, CDCl3) δ 7.35 (s, 5H), 7.17-7.35 (bm, 5H), 6.52 (bs, 1H), 5.93 (bd, J=8.1 Hz, 1H), 5.10 (s, 2H), 4.46 (bm, 1H), 3.50 (dd, J=13.9, 6.2 Hz, 2H), 2.92 (dd, J=17.0, 4.2 Hz, 1H), 2.78 (t, J=7.1 Hz, 2H), 2.57 (dd, J=17.0, 6.4 Hz, 1H), 1.42 (s, 9H); Mass Spectrum (NH3 -DCI, e/z, relative abundance) 444, (M+NH4)+, 100%; 427, (M+H)+, 4%.
Part B. Preparation of (S)-β-(O-t-butyl)-α-aspart-N-(2-phenylethyl)amide
A solution of (S)-N-(benzyloxycarbonyl)-β-(O-t-butyl)-α-aspart-N-(2-phenylethyl)amide (4.09 g, 9.58 mmol) in ethyl alcohol (30 mL) was hydrogenated under atmospheric pressure using 10% palladium on carbon catalyst (1.0 g) for 90 minutes. The catalyst was filtered and the filtrate concentrated in vacuo to give 2.80 g of an amber oil, which was purified by flash chromatography (5% MeOH/DCM), affording 2.13 g (76%) of the free amine as a solid product; 1 H NMR (300 MHz, CDCl3) δ 7.44(bs, 1H), 7.20-7.35 (m, 5H), 3.61 (dd, J=8.4, 3.7 Hz, 1H), 3.52 (dd, J=13.2, 7.0 Hz, 1H), 2.80-2.90 (m, 3H), 2.46 (dd, J=16.7, 8.4 Hz, 1H), 1.58 (bs, 2H), 1.45 (s, 9H); Mass Spectrum (ESI, e/z, relative abundance) 293, (M+H)+, 37%; 237, (M+H-C4 H8)+, 100%.
Part C. Preparation of Methyl 3-(4-methoxyiminophenyl)-(5R,S)-isoxazolin-5-ylacetate. Hydrochloride Salt
A suspension of 3-(4-cyanophenyl)-(5R,S)-isoxazolin-5-ylacetic acid (23.1 g, 100 mmol) in 200 mL of anhydrous methanol was chilled in an ice bath and dry HCl gas was bubbled through the reaction mixture until a clear solution was obtained. The total addition time was about three hours. The reaction flask was sealed and the reaction mixture was allowed to warm to room temperature, with stirring, over a period of about 24 hrs. At this point, the methanolic solution was poured into 600 mL of anhydrous ether, precipitating the product, and the resulting slurry was chilled to -25° C. for 21/2 hours. The slurry was then diluted with an additional 100 mL of chilled anhydrous ether. The precipitate was filtered, washed with two 100 mL portions of chilled anhydrous ether, and suction dried under nitrogen to afford 23.3 g (73%) of the hydrochloride salt; 1 H NMR (300 MHz, CDCl3) δ 12.9 (bs, 1H) 12.2 (bs, 1H), 8.46 (d, J=8.8 Hz, 2H), 7.86 (d, J=8.8 Hz, 2H), 5.20 (bm, 1H), 4.59 (s, 3H), 3.74 (s, 3H), 3.53 (dd, J=16.8, 10.6 Hz, 1H), 3.15 (dd, J=16.8, 7.7 Hz, 1H), 2.90 (dd, J=16.1, 6.2 Hz, 1H), 2.70 (dd, J=16.1, 7.3 Hz, 1H), 1.77 (bs, 1H); Mass Spectrum (NH3 -CI/DDIP, e/z, relative abundance) 277, (M+H)+, 100%.
Part D. Preparation of methyl 3-(4-amidinophenyl)-5R,S)-isoxazolin-5-ylacetate. Hydrochloride Salt
A suspension of methyl 3-(4-methoxyiminophenyl)-(5R,S)-isoxazolin-5-ylacetate hydrochloride (22.9 g, 73.0 mmol) in 500 mL of 1M ammonia in anhydrous methanol was stirred at room temperature for 14 hours during which time all solids dissolved. The solution was concentrated in vacuo to give 22.1 g (100%) of crude hydrochloride salt as a tan solid; 1 H NMR (300 MHz, CDCl3) δ 9.6-9,2 (b), 7.91 (d, J=8.8, 2H), 7.87 (d, J=8.8, 2H), 5.08 (bm, 1H), 3.64 (s, 3H), 3.3-3.1 (m, 2H), 2.8 (m, 2H); Mass Spectrum (ESI, e/z, relative abundance) 264, (M+H)+, 100%.
Part E. Preparation of Methyl 3-(4-N-Boc-amidinophenyl)isoxazolin-5-ylacetate
To a solution of 21.6 g (72.5 mmol) of methyl 3-(4-amidinophenyl)isoxazolin-5-ylacetate (prepared using the procedure of Example 434, Part D) in 350 ml DMF cooled with an ice bath was added 20.2 ml (145 mmol) of triethylamine and 17.4 g (79.8 mmol) of di-tert-butyl dicarbonate. The mixture was warmed to room temperature and stirred for 16 hours. The reaction mixture was poured into 1500 ml water while stirring. A while precipitate formed and was then filtered and dried on the filter under nitrogen to give 19.6 g (74.8%) of the title compound as a white solid. MS (ESI): m/e 362 (M+H)+ ; 306 (M+H-tBu)+. 1 H NMR (300 MHz, d6 -DMSO): δ 1.56 (s, 9H); 2.68 (dd, J=6.1, 6.1 Hz, 1H); 2.90 (dd, J=6.1, 6.1 Hz, 1H); 3.14 (dd, J=6.8, 6.8 Hz, 1H); 3.56 (dd, J=6.8, 6.8 Hz, 1H); 3.74 (s, 3H); 5.14 (m, 1H); 7.70 (d, J=8.4 Hz, 2H); 7.90 (d, J=8.4 Hz, 2H). 13 C NMR (60 MHz, d6 -DMSO): δ 28.46; 39.31; 39.58; 51.98; 77.89; 78.35; 126.91; 128.51; 132.79; 136.24; 156.86; 164.04; 165.76; 170.93.
Part F. Preparation of 3-(4-N-Boc-amidinophenyl)isoxazolin-5ylacetic Acid
To a solution of 18.95 g (52.4 mmol) of methyl 3-(4-N-Boc-amidinophenyl)isoxazolin-5-ylacetate (prepared using the procedure of Example 434, Part E) in 500 ml methanol was added 2.42 g (57.7 mmol) of lithium hydroxide monohydrate in 75 ml water at 22° C. The mixture was stirred at 22° C. for 16 hours and then filtered; the filtrate was then evaporated under reduced pressure to remove methanol. The residual aqueous phase was cooled with an ice bath and acidified with 6 N and 1 N HCl to pH=4. A white solid precipitated and it was left at -4° C. overnight. The solid was filtered and dried on the filter under nitrogen to give 17.74 g (97.4%) of the title compound as an off-white powder. MS (ESI): m/e 348 (M+H)+ ; 292 (M+H-tBu)+. 1 H NMR (300 MHz, d6 -DMSO): δ 1.50 (s, 9H); 2.68 (d, J=7.0 Hz, 2H); 3.22 (dd, J=7.2, 7.2 Hz, 1H); 3.62 (dd, J=6.8, 7.2 Hz, 1H); 5.04 (m, 1H); 7.78 (d, J=8.4 Hz, 2H); 7.94 (d, J=8.4 Hz, 2H). 13 C NMR (60 MHz, d6 -DMSO): δ 28.27; 39.30; 40.44; 78.39; 81.55; 126.87; 129.43; 132.78; 133.87; 156.76; 158.61; 165.58; 171.91.
Part G. Preparation of (S)-N-[.sup.α -(4-N-Boc-Amidinophenyl)-isoxazolin-5-(R,S)-ylacetyl]-β-(O-t-butyl)-.alpha.-aspart-N-(2-phenylethyl)amide
To a suspension of (S)-β-(O-t-butyl)-α-aspart-N-(2-phenylethyl)amide (0.30 g, 1.0 mmol), 3-(4-N-Boc-amidinophenyl)-isoxazolin-5-ylacetic acid (0.35 g, 1.0 mmol), and TBTU (0.32 g, 1.0 mmol) in EtOAc (20 mL), was added triethy amine (460 μL, 0.33 g, 1.0 mmol). The reaction mixture was stirred at room temperature for 4.5 hr. It was diluted with EtOAc (20 mL), washed with pH 4 buffer, water, 5% NaHCO3 and sat. NaCl, dried over anhydrous MgSO4, filtered, and concentrated in vacuo to give 0.58 g of solid. The crude product was purified by flash chromatography (100% EtOAc), affording 0.51 g (81%); 1 H NMR (300 MHz, CDCl3) δ 7.89 (t, J=8.1 Hz, 2H), 7.69 (m, 2H), 7.25-7.3 (m, 3H), 7.15-7.25 (m, 4H), 7.04 (d, J=8.4 Hz, 1H), 6.65-6.80 (dt, 1H), 5.10 (bm, 1H), 4.71 (bm, 1H), 3.4-3.7 (bm, 3H), 3.1-3.3 (octet, 1H), 2.75-2.95 (m, 3H), 2.5-2.65 (m, 3H), 1.56 (s, 9H), 1.44, (d, 9H); Mass Spectrum.(ESI, e/z, relative abundance) 622, (M+H)+, 100%.
EXAMPLE 435 Preparation of (S)-N.sup.α -[3-(4-Amidinophenyl)-isoxazolin-5-(R,S)-ylacetyl]-α-aspart-N-(2-phenylethyl)amide, Trifluoroacetic Acid Salt
A solution of (S)-N-[3-(4-N.sup.α -Boc-amidinophenyl)-isoxazolin-5-ylacetyl]-β-(O-t-butyl)-α-aspart-N-(2-phenylethyl)amide (160 mg, 0.26 mmol) in trifluoroacetic acid (10 mL) and DCM (10 mL) was stirred at room temperature for three days. The solution was concentrated in vacuo to give 150 mg of product; 1 H NMR (300 MHz, CDCl3) δ 9.40 (bs, 2H), 9.26 (bs, 2H), 8.33 (t, J=8.6, 1H), 7.85-8.0 (m, 1H), 7.88 (s, 4H), 7.3 (m, 1H), 7.28 (d, J=7.1, 2H), 7.20 (d, J=7.1, 2H), 5.07 (bm, 1H), 4.56 (bm, 1H), 3.5-3.6 (octet, 1H), 3.26 (bt, J=7.0, 2H), 3.2 (m, 1H), 2.70 (bt, J=7.0, 2H), 2.6-2.65 (bm, 2H), 2.4-2.5 (m, 2H); Mass Spectrum (ESI, e/z, relative abundance) 466, (M+H)+, 100%.
EXAMPLE 445 N2 -(β-Styrylsulfonyl)-N3 -[3-(4-amidino-phenyl)isoxazolin-5(R,S)-ylacetyl]-(S)-2,3-diaminopropionic Acid TFA Salt
Prepared according to Example 490a. MS (ESI, e/z, relative intensity): 500 (M+H)+, (100%).
EXAMPLES 473A AND 473B Resolution of Methyl N2 -3-methylphenylsulfonyl-N3 -[3-(4-amidinophenyl)-5S-ylacetyl]-S-2,3-diaminopropionate Trifluoroacetic Acid Salt and Methyl N2 -3-methylphenylsulfonyl-N3 -[3-(4-amidinophenyl)isoxazolin-5R-ylacetyl]-S-2,3-diaminopropionate Trifluoroacetic Acid Salt
The mixture was initially purified on a Pirkle DNBPG column using 10%HOAc/20%EtOH/70% hexane as the eluting solvent. The column temperature was maintained at 45° C., the flow rate at 1.5 ml/min, and the detector set at 280 nm. The diastereomers were then separated on a chiralcel OD-25×2cm column using an eluting solvent of 0.1%TFA/20%MeOH/80%CO2. The column temperature was maintained at 30° C., the flow rate at 13 ml/min, the pressure at 175 atm, and the detector was set at 280 nm. Injections were made on 23mg of sample. Over the two columns a total of 300 mg was injected giving 59 mg of the R isomer, Ex. 473A (HRMS calc'd for C23 H27 N5 O6 S 502.176031 Found: 502.175508) and 85 mg of the S isomer, Ex. 473B (HRMS calc'd for C23 H27 N5 O6 S 502.176031 Found: 502.176358).
EXAMPLE 473C N2 -3-methylphenylsulfonyl-N3 -[3-(4-amidinophenyl)isoxazolin-5S-ylacetyl]-S-2,3-diaminopropionic Acid
Part A: Methyl-N2 -3-methylphenylsulfonyl-N3 -[3-(4-cyanophenyl)isoxazolin-5S-ylacetyl]-S-2,3-diaminoprotionate
Into a solution of 3-(4-cyanophenyl)isoxazolin-5-S-ylacetic acid (1.82 g, 7.90 mmol, obtained as described in Es. 314A, part F) in DMF (50 ml) was added methyl-N2 -3-methylphenylsulfonyl-L-2,3-diaminopropionate HCl salt (2.77 g, 7.90 mmol), TBTU (2.53 g, 7.90 mmol), and Hunigs base (2.75 ml, 15.8 mmol). After stirring at room temperature for 16 hours, the reaction mixture was diluted with EtOAc (500 ml) and washed one time with water (200 ml), one time with sat'd NaHCO3 (200 ml), one time with 0.1N HCl (200 ml), dried (MgSO4), filtered, and concentrated. Column chromatography on silica gel using 10% EtOAc/hexane as the eluting solvent gave 1.99 g (52%) of the desired material as an off-white foam. 1 H NMR: (CDCl3): δ 7.81-7.78 (d, 2H, J=8.4 Hz); 7.16-7.67 (d, 2H, J=8.8 Hz); 7.61-7.58 (m, 2H); 7.39-7.37 (d, 2H, J=5.1 Hz); 6.35-6.30 (m, 1H); 5.54-5.52 (d, 1H, J=7.7 Hz); 5.18-5.17 (m, 1H); 4.00-3.96 (m, 1H); 3.62-3.50 (m, 3H); 3.57 (s, 3H); 3.27-3.19 (dd, 1H, J-7.7, 17.0 Hz); 2.78-2.70 (dd, 1H, J=5.9, 14.8 Hz); 2.64-2.57 (dd, 1H, J=6.6, 14.6 Hz); 2.42 (s, 3H).
Part B: Methyl-N2 -3-methylphenylsulfonyl-N3 -[3-(4-amidinophenyl)isoxazolin-5S-ylacetyl]-S-2,3-diaminopropionate hydrochloride
Methyl-N2 -3-methylphenylsulfonyl-N3 -[3-(4-cyanophenyl)-5S-ylacetyl]-S-2,3-diaminopropionate was dissolved in 100 ml absolute ethanol at 0° C. and a stream of HCl gas was bubbled through the solution for two hours. The reaction vessel was sealed and after sitting at room temperature for 16 hours the volatiles were removed in vacuo. The residue was then diluted with 100 ml of absolute ethanol, ammonium carbonate (9.6 g, 0.123 mol) was added and after stirring for 16 hours the reaction mixture was filtered and concentrated in vacuo. Column chromatography on silica using a gradient elution from 5%MeOH/CH2 Cl2 to 20%MeOH/CH2 Cl2 gave 0.762 g (37%) of the desired amidine as a white solid. 1 H NMR (CDCl3): δ 8.23-8.20 (m, 1H); 7.91-7.85 (m, 4H); 7.57-7.54 (m, 2H); 7.49-7.46 (m, 2H); 5.00-4.94 (m, 1H); 4.08-3.86 (m, 1H); 3.59-3.49 (m, 1H); 3.39 (s, 3H); 3.38-3.29 (m, 3H); 2.49 (s, 3H); 2.50-2.45 (m, 2H). HRMS: calc'd for C23 H27 N5 O6 S 502.176031 found 502.175992. [α]D =+48.88° (c=0.180, MeOH).
Part C: N2 -3-methylphenylsulfonyl-N3 -[3-(4-amidinophenyl)5(S)-yl]acetyl-S-2,3-diaminopropionic acid
The compound of Ex 473C, part B (0.077 g., 0.14 mmol) was dissolved in MeOH (4 ml). To the resulting solution was added a solution of lithium hydroxide (0.0066 g., 0.158 mmol) in water (4 ml) and the mixture was stirred overnight at room temperature. The methanol was removed by evaporation in vacuo, and the product precipitated from the aqueous as a white solid (0.026 g., 35%). HRMS calcd for C22 H25 N5 O6 S: 488.160381; found: 488.160827.
EXAMPLE 473D Methyl-N2 -3-methylphenylsulfonyl-N3 -[3-(4-amidinophenyl)isoxazolin-5R-ylacetyl]-S-2,3-diaminopropionate Hydrochloride
Part A: Methyl-N2 -3-methylphenylsulfonyl-N3 -[3-(4-cyanophenyl)-5R-ylacetyl]-S-2,3-diaminopropionate
This compound was synthesized from 3-(4-cyanophenyl)isoxazolin-5-(R)-ylacetic acid (3.07 g, 0.011 mol, obtained as described in Ex. 314B, part B) using the same procedure as for example 473C, part A. Yield 41%. Theory: C 57.02, H 4.99, N 11.56 Found: C 56.83, H 4.87, N 11.45.
Part B: Methyl-N2 -3-methylphenylsulfonyl-N3 -[3-(4-amidinophenyl)isoxazolin-5R-ylacetyl]-S-2,3-diaminopropionate hydrochloride
This compound was synthesized from Methyl-N2 -3-methylphenylsulfonyl-N3 -[3-(4-cyanophenyl)isoxazolin-5R-ylacetyl]-S-2,3-diaminopropionate using the same procedure as for example 473C, part B. Yield 49%. HRMS Calc'd for C23 H27 N5 O6 S 502.176031 Found: 502.174103.
EXAMPLE 478a N2 -2,4,6-trimethylphenylsulfonyl-N3 -[3-(4-amidinophenyl)-isoxazolin-5-(R,S)-ylacetyl]-(S)-2,3-diaminopropionic Acid TFA Salt
1 H NMR (DMSO-d6) δ: 9.37 (s, 2H), 9.06 (s,2H), 8.10 (q,J=6.22 Hz, 1H), 7.98(d, J=9.52 Hz, 1H), 7.87 (s,4H),6.98 (d, J=4.40 Hz, 2H), 4.99(m, 1H), 3.85 (m, 1H), 3.59-3.0 (m, 4H), 2.55 (s, 6H), 2.41 (m,2H), 2.23 (s, 3H) ppm; Mass Spectrum (ESI) m/z (M+H)+ 516.3 (100)%, High Res Mass Spectrum (M+H)+ calculated 516.190344, found 516.189999.
EXAMPLE 479a N2 -2-chlorophenylsulfonyl-N3 -[3-(4-amidinophenyl)-isoxazolin-5-(R,S)-ylacetyl]-(S)-2,3-diaminopropionic Acid
M.P. 138-140° C. 1 H NMR (DMSO-d6) δ: 9.39 (s, 2H), 9.27 (s, 2H) 8.30 (dd, J=4.40, 9.15 Hz 1H), 8.22 (m, 1H), 7.96 (d, J=6.95 Hz, 1H), 7.88 (s, 4H), 7.65 (m,2H), 7.59 (m 1H), 5.04 (m, 1H), 4.03 (m 1H), 3.58 (m 1H), 3.38 (m, 1H), 3.24 (m, 2H), 2.59 (dd, j=6.22, 14.28 Hz, 1H), 2.43 (m, 1H) ppm Mass Spectrum (ESI) m/z (M+H)+ 508.1 (100%), High Res Mass Spectrum (M+H)+ calculated 508.107096, found 508.106929.
EXAMPLE 485a N.sup.α -2,3,5,6-tetramethylthenylsulfonyl-N3 -[3-(4-amidinophenyl)-isoxazolin-5-(R,S)-ylacetyl]-(S)-2,3-diaminopropionic Acid TFA Salt
M.P.148-150° C., 1 H NMR (DMSO-d6) δ: 9.38 (s, 2H), 9.29 (s,2H), 8.09 (m, 1H), 7.97 (dd, J=4.40, 9.15 Hz, 1H), 7.85 (s, 4H), 7.15 (d, J=7.32 Hz, 1H), 4.98 (m, 1H), 3.88 (q, J=6.96, 15.75 Hz, 1H), 3.56 (m, 1H), 3.34-3.08 (m, 4H), 2.43 (s,6H), 2.39 (m, 1H), 2.19 (s,3H), 2.18 (s, 3H) ppm. Mass Spectrum (ESI) m/z (M+H)+ 530.2 (100%); High Res Mass Spectrum (M+H)+ calculated 530.208668; found 530.208357.
EXAMPLE 490a N2 -n-Propanesulfonyl-N3 -[3-(4-amidinophenyl)isoxazolin-5(R,S)-ylacetyl]-(S)-2,3-diaminopropionic Acid TFA Salt
Part A: Methyl N2 -n-Propanesulfonyl-N3 -Boc-(S)-2,3-diaminopropionate
To a solution of methyl N3 -Boc-(S)-2,3-diaminopropionate (prepared in Ex 20, Part C, 410 mg, 1.88 mmol)-in CH2 Cl2 (5 mL) at 0° C. was added propanesulfonyl chloride (0.21 mL, 1.9 mmol) and Et3 N (0.35 mL, 2.5 mmol) and the resulting mixture allowed to warm to room temperature overnight (18 h). The mixture was washed with 0.1 M HCl, sat. NaHCO3 and brine, dried (MgSO4), and concentrated to give 530 mg (87%) of the desired sulfonamide as a viscous oil; CIMS (e/z, relative intensity): 342 (M+H)+, 100%.
Part B: Methyl N2 -n-Propanesulfonyl-(S)-2,3-diaminopropionate Hydrochloride Salt
To neat methyl N2 -n-propanesulfonyl-N3 -Boc-(S)-2,3-diaminopropionate (520 mg, 1.60 mmol) was added 4 M HCl/dioxane (5 mL, 20 mmol). The resulting solution was stirred at room temperature for 4 h, then it was concentrated in vacuo, giving an oil. Trituration with ether (3×10 mL) followed by drying under vacuum afforded 383 mg (92%) of the desired amine; CIMS (e/z, relative intensity): 225 (M+H)+, 100%.
Part C: Methyl N2 -n-propanesulfonyl-N3 -[3-(4-(N-t-butoxycarbonylamidino)phenyl)isoxazolin-5(R,S)-ylacetyl]-(S)-2,3-diaminopropionate
To a suspension of 3-(4-N-Boc-amidinophenyl)isoxazolin-5-ylacetic acid (prepared in Example 32, 252 mg, 0.725 mmol), methyl N2 -n-propanesulfonyl-(S)-2,3-diaminopropionate hydrochloride (189 mg, 0.726 mmol) in DMF (5 mL) was added Et3 N (0.30 mL, 2.2 mmol) and TBTU (233 mg, 0.726 mmol). The resulting mixture was stirred for 4 h at room temperature, then was diluted with EtOAc (30 mL). It was washed with water (4×20 mL), sat. NaHCO3 (30 mL), sat. NaCl and dried (MgSO4). Concentration in vacuo followed by placing the material under vacuum until constant weight was achieved afforded 292 mg (73%) of the desired amide; MS (ESI, e/z, relative intensity): 554 (M+H)+, 100%.
Part D: Methyl N2 -n-Propanesulfonyl-N3 -[3-(4-amidinophenyl)isoxazolin-5(R,S)-ylacetyl]-(S)-2,3-diaminopropionate TFA Salt
To a solution of methyl N2 -n-propanesulfonyl-N3 -[3-(4- (N- t-butoxycarbonylamidino)phenyl)isoxazolin-5(R,S)-ylacetyl]-(S)-2,3-diaminopropionate (284 mg, 0.513 mmol) in CH2 Cl2 (4 mL) was added TFA (2 mL, 26 mmol). After 2 h at room temperature, the solution was concentrated in vacuo and the residue triturated with ether (3×5 mL). The resulting white powder was then placed under vacuum until constant weight was achieved, giving 260 mg (89%) of the desired benzamidine; MS (ESI, e/z, relative intensity): 454 (M+H)+, 100%.
Part E: N2 -n-Propanesulfonyl-N3 -[3-(4-amidinophenyl)isoxazolin-5(R,S)-ylacetyl]-(g)-2,3-diaminopropionic Acid TFA Salt
To a solution of methyl N2 -n-propanesulfonyl-N3 [3-(4-amidinophenyl)isoxazolin-5(R,S)-ylacetyl]-(S)-2,3-diaminopropionate (100 mg, 0.176 mmol) in MeOH (1 mL) was added 0.5 M LiOH (0.5 mL, 0.25 mmol) and the reaction stirred at room temperature overnight (18 h). The resulting mixture was concentrated in vacuo, redissolved in water and the pH adjusted to 4 using 1 M HCl. Purification on reversed phase HPLC gave 10 mg (10%) of the desired carboxylic acid; MS (ESI, e/z, relative intensity): 440 (M+H)+, (100%).
EXAMPLE 492a N2 -p-isopropylphenylsulfonyl-N3 -[3-(4-amidinophenyl)isoxazolin-5-(R,S)-ylacetyl]-(S)-2,3-diaminopropionic Acid TFA Salt
1 HNMR (DMSO) δ: 9.37(1H, s), 9.09(1H, s), 8.15(2H, m), 8.78(4H, d, J=1.465 Hz), 7.09(2H, d, J=8.423 Hz), 7.44(2H, m), 4.98(1H, m), 3.93(1H, m), 3.59(2H, m), 3.50(2H, m), 3.22(2H, m), 2.98(1H, m),2.45(2H, m), 1.22(6H, m)ppm; ESI mass spectrum 516.3 (M+H, 100)+ free base.
EXAMPLE 496 Methyl N2 -(2,2-diphenyl-1-ethenesulfonyl)-N3 -[3-(4-amidinophenyl)isoxazolin-5-(R,S)-ylacetyl]-(S)-2,3-diaminoeropionate, Trifluoroacetic Acid Salt
Part A: Methyl N2 -(2,2-diphenyl-1-ethenesulfonyl)-N3 -Boc-(S)-2,3-diaminopropionate.
To a mixture of methyl N3 -Boc-(S)-2,3-diaminopropionate (255 mg, 1.17 mmol) and 2,2-diphenylethylenesulfonyl chloride (Hasegawa and Hirooka, J. Chem. Soc. Japan 48, 1513-1518 (1975); 391 mg, 1.40 mmol) in methylene chloride (10 mL) cooled in an ice bath was added triethylamine (0.25 mL, 1.76 mmol). After 22 h, the mixture was concentrated and flash chromatographed (6:4 toluene/ethyl acetate) to provide 240 mg (46%) of product. NMR (CDCl3) δ 7.42-7.20 (10H), 6.81 (s, 1H), 5.24 (bd, 1H), 4.87 (bs, 1H), 3.95 (q, 1H), 3.72 (s, 3H), 3.50-3.42 (2H), 1.44 (s, 9H); mass spec (NH3 -CI) m/z 466.54 (M+NH4+, 100%).
Part B: Methyl N2 -(2,2-diphenyl-1-ethenesulfonyl)-(S)-2,3-diaminopropionate TFA salt.
The product of Part A (210 mg, 0.468 mmol) was dissolved in 5 mL of methylene chloride and 3 mL TFA. After 1 hour, the solution was concentrated to give an oily product. (222 mg, 100%). NMR (DMSO-d6) δ 8.02 (bs, 3H), 7.40 (m, 5H), 7.23 (m, 4H), 7.00 (s, 1H), 4.26 (m, 1H), 3.71 (s, 3H), 3.20 (m, 1H), 2.98 (m, 1H).
Part C: Methyl N2 -(2,2-diphenyl-1-ethenesulfonyl)-N3 -[3-(4-N-Boc-amidinophenyl)isoxazolin-5-(R,S)-ylacetyl]-(S)-2,3-diaminopropionate.
The product of part B (220 mg, 0.46 mmol) was reacted with 3-(4-N-Boc-amidinophenyl)-isoxazolin-5-ylacetic acid (from Example 434 , part F; 160 mg, 0.46 mmol), according to the procedure of example 651, Part A, to provide the title product (215 mg, 68%). NMR (CDCl3) δ 7.84 (m, 2H), 7.64 (m,2H), 7.40-7.18 (10H), 6.75 (s, 1H), 6.30 (m, 1H), 5.30 (m, 1H), 5.04 (m,1H), 4.00 (1H), 3.78 (s,3H), 3.62-3.40 (4H), 3.10 (m, 1H), 2.70-2.50 (2H), 2.04 (s, 1H), 1.58 (s, 9H); mass spec (ESI) m/z 690.2 (M+H+, 100%).
Part D: Methyl N2 -(2,2-diphenyl-1-ethenesulfonyl)-N3 -[3-(4-amidinophenyl)isoxazolin-5-(R,S)-ylacetyl]-(S)-2,3-diaminopropionate, trifluoroacetic acid salt
The product of part C (210 mg, 0.30 mmol) was dissolved in methylene chloride (3 mL) and treated with trifluoroacetic acid (1 mL) according to the procedure of example 651, Part B, to provide the title product (150 mg, 80%). NMR (DMSO-d6) δ 9.39 (bs,2H), 9.05 (bs,2H), 8.22 (m, 1H), 8.00 (m, 1H), 7.85 (s,4H), 7.40 (m,6H), 7.20 (m,4H), 6.89 (s, 1H), 5.00 (m, 1H), 4.00 (m, 1H), 3.70-3.18 (5H), 3.62 (2s,3H); mass spec (ESI) m/z 590.2 (M+H+, 100%)
EXAMPLE 511 Methyl N2 -(N,N-dimethylsulfamoyl)-N3 -[3-(4-amidinophenyl)isoxazolin-5-(R,S)-ylacetyl]-(S)-2,3-diaminopropionate, Trifluoroacetic Acid Salt
Part A: Methyl N2 -(N,N-dimethyl sulfamoyl)-N3 -Boc-(S)-2,3-diaminopropionate.
To a mixture of methyl N3 -Boc-(S)-2,3-diaminopropionate (400 mg, 1.80 mmol) and Dimethylsulfamoyl chloride (0.24 mL, 2.20 mmol) in methylene chloride (10 mL) cooled in an ice bath was added triethylamine (0.38 mL, 2.20 mmol). After 18 h, the mixture was concentrated and flash chromatographed (6:4 toluene/ethyl acetate) to provide 283 mg (49%) of product. NMR (CDCl3) δ 5.23 (bd, 1H), 4.90 (m, 1H), 4.06 (m, 1H), 3.80 (s, 3H), 3.52 (bt, 2H), 2.80 (s,6H), 1.42 (s, 9H); mass spec (NH3 -CI) m/z 343.0 (M+NH4 +, 100%).
Part B: Methyl N2 -(N,N-dimethyl sulfamoyl)-(S)-2,3-diaminopropionate TFA salt.
The Product of Part A was dissolved in 5 mL of methylene chloride and 3 mL TFA. After 1 hour, the solution was concentrated to give an oily product (294 mg, 100%). NMR (DMSO-d6) δ 6.52 (bs, 2H), 4.4-3.9 (2H), 3.8 (bs, 3H), 2.93 (bs, 6H).
Part C: Methyl N2 -(N,N-dimethyl sulfamoyl)-N3 -[3-(4-N-Boc-amidinophenyl)isoxazolin-5-(R,S)-ylacetyl]-L-2,3-diaminoiroDionate.
The product of part B (200 mg, 0.61 mmol) was reacted with 3-(4-N-Boc-amidinophenyl)isoxazolin-5-ylacetic acid (from Example 434, part F; 212 mg, 0.61 mmol), according to the procedure of Example 651, Part A, to provide the title product (203 mg, 61%). NMR (CDCl3) δ 7.78 (m, 2H), 7.42 (bt, 2H), 7.00 (m, 1H), 5.92 (m, 1H), 5.04 (m, 1H), 3.80 (2s, 3H), 3.64 (m, 2H), 3.40 (m, 1H), 3.05 (m, 1H), 2.80 (2s, 6H), 2.74 (m, 1H), 2.60 (m, 1H), 2.02 (s, 3H), 1.60 (s, 9H); mass spec (ESI) m/z 555.1 (M+H+, 100%).
Part D: Methyl N2 -(N,N-dimethyl sulfamoyl)-N3 -[3-(4-amidinophenyl)isoxazolin-5-(R,S)-ylacetyl]-L-2,3-diaminopropionate, trifluoroacetic acid salt
The product of part C (183 mg, 0.329 mmol) was dissolved in methylene chloride (3 mL) and treated with trifluoroacetic acid (1 mL) according to the procedure of example 651, Part B, to provide the title product (159 mg, 85%). NMR (DMSO-d6) δ 9.40 (bs, 2H), 9.00 (bs, 2H), 8.22 (m, 1H), 7.82 (s, 4H), 5.00 (m, 1H), 3.95 (m, 1H), 3.68 (2s, 3H), 3.60 (m, 2H), 3.20 (m, 4H), 2.80 (s, 6H); mass spec (ESI) m/z 455.1 (M+H+, 100%).
EXAMPLE 512 Methyl N2 -(m-toluenesulfonyl)-N3 -[3-(4-amidino-2-fluorophenyl)isoxazolin-5-ylacetyl]-S-2,3-diaminopropionate Hydrochloric Acid Salt
Part A: 3-Fluoro-4-methylbenzamide
3-Fluoro-4-methylbenzoic acid (10 g, 65 mmol) was boiled in thionyl chloride (100 ML) under a drying tube for 2.5 h. The excess SOCl2 was removed by distillation. The oily acid chloride product was diluted with CH2 Cl2 (100 mL) and cooled in an ice bath. Conc. aq. NH3 (20 mL) was added dropwise, and stirring continued at 0° C. for 0.5 h. The CH2 Cl2 was removed in vacuo, then the residue was diluted with EtOAc. The mixture was extracted with sat. aq. Na2 CO3 (2x), H2 O, and brine, dried (MgSO4), and concentrated to yield 9.9 g of a pale yellow solid; mp 161°-163° C.; IR(KBr) 3382, 1654 cm-1 ; Anal. Calc. for C8 H8 FNO: C, 62.74; H, 5.27; N, 9.15; F, 12.40. Found: C, 62.66; H, 5.17; N, 9.12; F, 12.28.
Part B: 3-Fluoro-4-methylbenzonitrile
A solution of trichloroacetyl chloride (7.3 mL, 65 mmol) in CH2 Cl2 (20 mL) was added dropwise over 0.5 h to a solution/suspension of the Part A amide (9.0 g, 59 mmol) and Et3 N (17 mL, 120 mmol) in CH2 Cl2 (80 mL) at 0° C. After 40 min, the mixture was concentrated in vacuo, then diluted with Et2 O. This solution was extracted with 1 M HCl, sat. aq. NaHCO3, H2 O, and brine, then dried (MgSO4), and concentrated to yield 7.8 g of a tan solid; mp 45-47° C.; IR(KBr) 2232 cm-1 ; HRMS, e/z Calc. for (M+H)+ : 135.0484. Found: 135.0482.
Part C: 2-Fluoro-4-cyanobenzylbromide
N-Bromosuccinimide (9.6 g, 54 mmol) and the part B substrate (7.3 g, 54 mmol) were heated under reflux in CCl4 (100 mL) under N2 with irradiation with a high intensity visible lamp for 2 h. After cooling to ambient temp., the mixture was filtered through a Celite pad and concentrated in vacuo. The crude product was recrystallized from hot cyclohexane (4x) to yield 4.5 g of off-white needles; mp 75-77° C.; IR(KBr) 2236 cm-1. RMS, e/z Calc. for (M+H)+ : 213.9668. Found: 213.9660.
Part D: 2-Fluoro-4-cyanobenzaldehyde
The part C benzyl bromide (3.68 g, 17 mmol), trimethylamine N-oxide dihydrate (7.6 g, 68 mmol), CH2 Cl2 (15 mL), and DMSO (30 mL) were stirred at 0° C. for a few h, slowly warming to ambient T overnight. The mixture was diluted with water (30 mL) and brine (30 mL), and extracted with Et2 O (4x). The combined organics were washed with brine, dried (MgSO4), and concentrated to yield 1.1 g of a yellow solid; IR(KBr) 2238, 1706 cm-1 ; HRMS, e/z Calc. for (M+H)+ : 150.0355. Found: 150.0341.
Part E: 2-Fluoro-4-cyanobenzaldoxime
The part D aldehyde (1.1 g, 7.4 mmol), hydroxylamine hydrochloride (1.0 g, 15 mmol), K2 CO3 (1.0 g, 7.4 mmol), water (1 mL), and MeOH (10 mL) were heated under reflux for 2.25 h. After brief cooling, the mixture was diluted with water, and the insoluble product was collected by filtration, then rinsed with more water. Drying under high vacuum provided 0.94 g of a pale yellow amorphous solid; mp 179-182° C.; IR(KBr) 3256, 2236, 1556 cm-1 ; HRMS, e/z Calc. for (M+H)+ : 165.0464. Found: 165.0455.
Part F: Methyl 3-(4-cyano-2-fluorophenyl)isoxazolin-5-ylacetate
The part E oxime was allowed to react with Clorox and methyl vinylacetate in the usual way to afford the isoxazoline as a yellow solid in 32% yield; mp 92-94° C.; IR(KBr) 2240, 1746 cm-1 ; HRMS, e/z Calc. for (M+H)+ : 263.0832. Found: 263.0818. Anal. Calc. for C13 H11 FN2 O3 : C, 59.54; H, 4.23; N, 10.68; F, 7.24. Found: C, 59.84; H, 4.31; N, 10.53; F, 7.26.
Part G: Methyl N2 -(m-toluenesulfonyl)-N3 -[3-(4-tert-butyloxycarbonylamidino-2-fluorophenyl)isoxazolin-(R,S)-5-ylacetyl-(S)-2,3-diaminopropionate.
The part F intermediate was converted to the title compound by the usual sequence of steps: Pinner amidine synthesis, amidine BOC protection, ester saponification, and condensation with the 2,3-diaminopropionate sulfonamide ester; MS (DCI, NH3) 620 (M+H), 520.
Part H: Methyl N2 -(m-toluenesulfonyl)-N3 -[3- (4-amidino-2-fluorophenyl)isoxazolin-(R,S)-5-ylacetyl-(S)-2,3-diaminoeropionate hydrochloric acid salt.
The BOC group was removed from the part G intermediate by treatment with 4M HCl in dioxane to provide a yellow gum; HRMS, e/z Calc. for (M+H)+ : 520.1666. Found: 520.1675.
EXAMPLE 512A N2 -(m-Toluenesulfonyl)-N3 -[3- (4-amidino-2-fluorophenyl)isoxazolin-(R)-5-ylacetyl-(S)-2,3-diaminopropionate Hydrochloric Acid Salt
Part A: N2 -(m-Toluenesulfonyl)-N3 -[3-(4-tert-butyloxycarbonylamidino-2-fluorophenyl)isoxazolin-(R,S)-5-ylacetyl-(S)-2,3-diaminopropionate.
The intermediate from Example 512, Part G (0.60 g, 0.97 mmol) was saponified using lithium hydroxide hydrate (61 mg, 1.45 mmol) in water (1 mL) and methanol (1 mL) at room temperature for 3 d. The mixture was extracted with ethyl acetate, the aqueous layer was acidified with pH 4 buffer, and it was extracted with ethyl acetate. The extracts were dried and concentrated to 0.427 g of a clear glass. This material was flashed chromatographed using a methanol/chloroform gradient solvent system, starting with chloroform and progressing through 2%, 10%, 15%, and 20% methanol/chloroform to give 0.360 g (57%) of a clear glass. 1 H NMR (DMSO-d6, 300 MHz) δ 9.09 (br, 1H), 7.88-7.80 (m, 3H), 7.60-7.56 (m, 2H), 7.47-7.42 (m, 2H), 5.00-4.97 (m, 1H), 3.62-3.57 (m, 1H), 3.29-3.16 (m, 4H), 2.58-2.43 (m, 2H), 2.37 (s, 3H), 1.45 (s, 9H). HRMS (FAB, glycerol) Calc. for (M+H)+ : 606.2034. Found: 606.2043.
Part B: N2 -(m-Toluenesulfonyl)-N3 -[3-(4-amidino-2-fluorophenyl)isoxazolin-(R)-5-ylacetyl-(S)-2,3-diaminopropionate hydrochloric acid salt.
The intermediate from Part A (0.344 g, 0.57 mmol) was dissolved in 4M HCl in dioxane and stirred at room temperature for 21.5 h. The solution was diluted with ether and the precipitated white solid was collected and dried, yielding 0.367 g. This material was subjected to super critical fluid chiral Prep HPLC on a Chiral OG 2 in×25 cm column using 0.1% TFA, 25% methanol, 75% carbon dioxide as eluent at a flow rate of 20 mL/min to separate the isoxazoline isomers. The second eluting, (R,S), isomer was obtained as a white solid. 1 H NMR (DMSO-d6, 300 MHz) δ 12.81 (br, 1H), 9.53 (s, 1.5H), 9.29 (s, 1.5H), 8.17 (m, 2H), 7.95 (t, J=7.7 Hz, 1H), 7.86 (d, J=12.0 Hz, 1H), 7.40 (d, J=9.5 Hz, 1H), 7.60-7.56 (m, 2H), 7.46-7.41 (m, 2H), 4.97-4.93 (m, 1H), 3.88-3.86 (m, 1H), 3.59-3.55 (m, 1H), 3.42-3.14 (m, 3H), 2.52-2.45 (m, 1H), 2.41-2.33 (m, 4H). HRMS (FAB, glycerol) Calc. for (M+H)+ : 506.1510. Found: 506.1494.
EXAMPLE 513 Methyl N2 -(n-butyloxycarbonyl)-N3 -[3-(3-amidinopyrid-6-yl)isoxazolin-5-ylacetyl]-S-2,3-diaminopropionate Hydrochloric Acid Salt
Prepared using methods described in Ex. 514 to provide a pale yellow powder; mp 90-110° C. (dec); HRMS, e/z Calc. for (M+H)+ : 449.2149. Found: 449.2140.
EXAMPLE 514 Methyl N2 -(m-toluenesulfonyl)-N3 -[3-(3-amidinopyrid-6-yl)isoxazolin-5-ylacetyl]-S-2,3-diaminopropionate Hydrochloric Acid Salt
Part A: 3-cyano-6-pyridaldoxime
5-Cyano-2-picoline (25 g, 0.21 mol) and I2 were heated under reflux in DMSO (200 mL) for 1 h. After cooling to RT, hydroxylamine hydrochloride (16 g, 0.23 mol), K2 CO3 (29 g, 0.21 mol), and water (21 mL) were added. The resulting mixture was heated to 80° C. for 2.5 h, cooled, diluted with water (100 mL) and much acetone, and absorbed onto silica gel by concentration. Chromatography on silica gel, eluting with 0% to 50% EtOAc in hexane, afforded 12.2 g of a tan solid; mp 204-207° C. (dec); HRMS, e/z Calc. for (M+H)+ : 148.0511. Found: 148.0516.
Part B: Methyl 3-(3-cyanoeyrid-6-yl)isoxazolin-5-ylacetate
The oxime of Ex. 514, part A was converted to the isoxazoline as described in Ex. 516, part B in 76% yield as a yellow solid; mp 97-98° C.; HRMS, e/z Calc. for (M+H)+ : 246.0879. Found: 246.0881. Anal. Calc. for C12 H11 N3 O3 : C, 58.77; H, 4.52; N, 17.13. Found: C, 58.74; H, 4.51; N, 17.11.
Part C: Methyl 3-(3-t-butyloxycarbonylamidinoyrid-6-yl)isoxazolin-5-ylacetate
The nitrile of Ex. 514, part B was converted to the amidine as described in the method of Ex. 516, parts D & E (except that 0.6 eq. NaOMe was required), and BOC protected in standard fashion to afford, after purification, a yellow solid; mp 143° C. (gas evolves); HRMS, efz Calc. for (M+H)+ : 363.1668. Found: 363.1675. Anal. Calc. for C17 H22 N4 O5 : C, 56.35; H, 6.12; N, 15.46. Found: C, 56.35; H, 6.10; N, 15.39.
Part D: Lithium 3-(3-t-butyloxycarbonylamidinopyrid-6-yl)isoxazolin-5-ylacetate
The ester of Ex. 514, part C was saponified and lyophilized as described in the method of Ex. 516, part F to give a colorless amorphous solid quantitatively; mp >230° C.; HRMS, e/z Calc. for conjugate acid (M+H)+ : 349.1512. Found: 349.1527.
Part E: Methyl N2 -(m-toluenesulfonyl)-N3 -[3-(3-tert-butyloxycarbonylamidinopyrid-6-yl)isoxazolin-(R,S)-5-ylacetyl]-(S)-2,3-diaminopropionate.
The Part D lithium carboxylate was condensed with methyl N2 -(m-toluenesulfonyl)-(S)-2,3-diaminopropionate hydrochloride using conditions described above to give a yellow foam. HRMS, e/z Calc for (M+H)+ : 603.2237. Found: 603.2223.
Part F: Methyl N2 -(m-toluenesulfonyl)-N3 -[3-(3-amidinopyrid-6-yl)isoxazolin-(R,S)-5-ylacetyl]-(S)-2,3-diaminopropionate hydrochloric acid salt.
The protected amidine of Part E was treated with 4M HCl in dioxane to provide a yellow solid; mp 90° C. (dec); HRMS, e/z Calc. for (M+H)+ : 503.1713. Found: 503.1718.
EXAMPLE 514A N2 -(m-Toluenesulfonyl)-N3 -[3-(3-amidinopyrid-6-yl)isoxazolin-(R)-5-ylacetyl]-(S)-2,3-diaminopropionic Acid Trifluoroacetic Acid Salt
Part A: Lithium N2 -(m-toluenesulfonyl)-N3 -[3-(3-tert-butyloxycarbonylamidinopyrid-6-yl)isoxazolin-(R,S)-5-ylacetyl]-(S)-2,3-diaminopropionate.
The methyl ester of Example 514, Part E (0.16 g, 0.27 mmol) was saponified by stirring with 0.5 M LiOH (0.54 mL, 0.27 mmol) in methanol (2 mL) at room temperature. The mixture was concentrated in vacuo to give 0.16 g (99%) of a tan solid; HRMS, e/z Calc for (M+H)+ : 589.2081. Found: 589.2086.
Part B: N2 -(m-Toluenesulfonyl)-N3 -[3-(3-amidinopyrid-6-yl)isoxazolin-(R)-5-ylacetyl]-(S)-2,3-diaminopropionic acid trifluoroacetic acid salt.
The lithium salt of Part A was treated with 4M HCl in dioxane to give a tan foam. This material was purified by Prep reverse phase HPLC on a Vydac C18 2×25 cm column using a gradient solvent system starting with 0.05% TFA in water progressing to 80:20 0.05% TFA in water: 0.05% TFA in acetonitrile over 50 m, the purified material was subjected to super critical fluid Prep chiral HPLC on a Chiral OG 2 in×25 cm column using 0.1% TFA, 25% methanol, 75% carbon dioxide as elutant at a flow rate of 20 mL/min to separate the isoxazoline isomers. The second eluting, (R,S), isomer was resubmitted to reverse phase Prep HPLC as above to give the title compound as a tan solid. 1 H NMR (DMSO-d6, 300 MHz) δ 2.31 (dd, J=15.0, 7.0 Hz, 1H, partially obscured), 2.37 (s, 3H), 2.48-2.59 (m, 1H, under DMSO), 3.02-3.15 (m, 1H), 3.22 (dd, J=17.6, 10.6 Hz, 1H), 3.32-3.42 (m, 1H, under water peak), 3.55 (dd, J=17.6, 10.6 Hz, 1H), 3.82-3.92 (m, 1H), 4.98-5.11 (m, 1H), 7.39-7.49 (m, 2H), 7.54-7.61 (m, 2H), 8.08-8.15 (m, 3H), 8.25 (dd, J=8.4, 2.2 Hz, 1H), 9.01 (d, J=1.8 Hz, 1H), 9.24 (br s, 2H), 9.53 (br s, 2H), 12.78 (very br s, 1H). MS (ESI) 489 (M+H, 65), 288 (100), 245 (27).
EXAMPLE 515 Methyl N2 -(n-butyloxycarbonyl)-N3 -[3-(2-amidinopyrid-5-yl)isoxazolin-5-ylacetyl]-S-2,3-diaminopropionate Hydrochloric Acid Salt
In similar fashion to the method described in Ex. 516, the compound of Ex. 514, part E was coupled with methyl N2 -(n-butyloxycarbonyl)-2,3-diaminopropionate hydrochloride using-conditions described above, followed by BOC deprotection with 4 M HCl/dioxane to yield a pale yellow powder; HRMS, e/z Calc. for (M+H)+ : 449.2149. Found: 449.2154.
EXAMPLE 516 Methyl N2 -(m-toluenesulfonyl)-N3 -[3- (2-amidinopyrid-5-yl)isoxazolin-5-ylacetyl]-S-2,3-diaminopropionate Hydrochloric Acid Salt
Part A: 2-Chloro-5-pyridaldoxime
2-Chloro-5-formylpyridine (2.1 g, 15 mmol) was condensed with hydroxylamine hydrochloride in the usual way to give the oxime, 1.5 g, as a yellow crystalline solid; mp 171-175° C. (dec); HRMS, e/z Calc. for (M+H)+ : 157.0169. Found: 157.0175.
Part B: Methyl 3-(2-chloropyrid-5-yl)isoxazolin-5-ylacetate
Sodium hypochlorite (5% wt, 20 mL) was added dropwise over 1.75 h to a mixture of the part A oxime (1.13 g, 7.2 mmol), methyl vinylacetate (70% purity, 3.0 g, 21 mmol), CH2 Cl2 (40 mL), and DMF (4 mL) with stirring at ambient temperature. The CH2 Cl2 was evaporated, and the mixture was diluted with EtOAc, extracted with water (5x) and brine, then dried (MgSO4), filtered, and concentrated. Chromatography on silica gel, eluting with 0% to 70% EtOAc in hexane, afforded 1.4 g of a solid; mp 94-96° C.; HRMS, e/z Calc. for (M+H)+ : 255.0536. Found: 255.0531.
Part C: Methyl 3-(2-cyanopyrid-5-yl)isoxazolin-5-ylacetate
The part B chloropyridine (0.51 g, 2.0 mmol), zinc cyanide (0.23 g, 2.0 imol), Pd(PPh3)4 (0.12 g, 0.10 mmol), and DMF (2 mL) were heated to 80° C. under N2 for 3 days. After cooling and concentration, the mixture was preabsorbed onto silica gel by concentration from CHCl3. Chromatography on silica gel, eluting with 0% to 90% EtOAc in hexane afforded 0.28 g of a pale yellow solid; mp 115-116° C.; HRMS, e/z Calc. for (M+H)+ : 246.0879. Found: 246.0880. Anal. Calc. for C12 H11 N3 O3 : C, 58.77; H, 4.52; N, 17.13. Found: C, 58.68; H, 4.48; N, 16.90.
Part D: Methyl 3-(2-amidinopyrid-5-yl)isoxazolin-5-ylacetate formic acid salt
The part C cyanopyridine (0.47 g, 1.9 mmol) and sodium methoxide (prepared in situ from Na metal, 4 mg, 0.2 mmol were stirred in dry MeOH (6 mL) at ambient temperature for 16 h, after which 1 H NMR analysis of a reaction aliquot indicated complete formation of methyl imidate [note 9.25 (s, 1H) and 3.92 (s, 3H)]. Ammonium formate (0.60 g, 9.5 mmol) was added to the reaction mixture, and stirring continued for 7 h. The mixture was absorbed onto silica gel by concentration in vacuo. Chromatography on silica gel, eluting with 0% to 20% MeOH in CHCl3, and concentration afforded 0.61 g of the amidine as an off-white solid; mp 180-182° C. (dec); HRMS, e/z Calc. for (M+H)+ : 263.1144. Found: 263.1148.
Part E: Methyl 3-(2-t-butyloxycarbonylamidinopyrid-5-yl)isoxazolin-5-ylacetate
The part D amidine was BOC protected in standard fashion to afford, after silica gel chromatographic purification, a 41% yield of a colorless foam; HRMS, e/z Calc. for (M+H)+ : 363.1668. Found: 363.1682.
Part F: Lithium 3-(2-t-butyloxycarbonylamidinopyrid-5-yl)isoxazolin-5-ylacetate
The part E methyl ester (0.37 g, 1.0 mmol) was saponified by stirring with 0.5 M LiOH in MeOH at RT. The MeOH was removed in vacua, then the aqueous mixture was frozen and lyophilized to produce a pale yellow solid quantitatively; HRMS, e/z Calc. for conjugate acid (M+H)+ : 349.1512. Found: 349.1531.
Part G: Methyl N2 -(m-toluenesulfonyl)-N3 -[3-(2-amidinopyrid-5-yl)isoxazolin-5-ylacetyl]-S-2,3-diaminopropionate hydrochloric acid salt
The part F lithium carboxylate was condensed with methyl N2 -(m-toluenesulfonyl)-2,3-diaminopropionate hydrochloride using conditions described above, followed by standard BOC deprotection with 4 M HCl/dioxane to yield a yellow amorphous solid; HRMS, e/z Calc. for (M+H)+ : 503.1713. Found: 503.1707.
EXAMPLE 516A N2 -(m-Toluenesulfonyl)-N3 -[3-(2-amidinopyrid-5-yl)isoxazolin-(R,S)-5-ylacetyl]-(S)-2,3-diaminopropionic Acid Trifluoroacetic Acid Salt
The methyl ester of Example 516, Part G (31.4 mg, 54.6 nmol) was dissolved in 6M aqueous hydrochloric acid (1 mL) and the mixture was stirred at room temperature for 44 h. The yellow solution was concentrated and subjected to Prep reverse phase HPLC as described in Example 514A, Part B to give 25.0 mg (75%) of a white solid. mp 158.5-161.5° C. 1 H NMR (DMSO-d6, 300 MHz) δ 2.31-2.44 (m, 1H), 2.37, 2.38 (singlets, 3H), 2.50-2.60 (m, 1H, under DMSO), 3.00-3.10 (m, 0.5H), 3.12-3.36 (m, 2H), 3.38-3.48 (m, 0.5H), 3.60 (ddd, J=17.2, 10.6, 5.9 Hz, 1H), 3.85-3.95 (m, 1H), 4.95-5.11 (m, 1H), 7.39-7.45 (m, 2H), 7.52-7.60 (m, 2H), 8.10-8.22 (m, 2H), 8.28-8.40 (m, 2H), 9.06 (s, 1H), 9.37 (br s, 2H), 9.60 (br s, 2H). MS (ESI) 489 (M+H, free base, 100), 214 (17).
EXAMPLE 528a N2 -o-Bromophenylcarbonyl-N3 -[3-(4-amidinophenyl)isoxazolin-5-(R,S)-ylacetyl]-(S)-2,3-diaminopropionic Acid
The title compound was obtained as its TFA salt from readily accessible N2 -amino-3-[(4-tertbutyloxycarbonylamidino)phenylisoxazolin-5-(R,S)-ylacetyl]-(S)-2,3-diamino-tertbutylpropionate by common acylation techniques with 2-bromobenzoyl chloride. Removal of the tert-butyl protecting groups with TFA afforded the desired product as colorless crystals. M.P. 172-174° C.; 1 H NMR (DMSO d6) δ: 7.80(d, J=8Hz, 2H), 7.51-7.63(m, 3H), 7.28 (m, 2H), 7.12 (dd, 1H), 6.61 (m, 1H), 5.05 (m, 1H), 4.81(q, 1H), 3.80 (d, 3H), 3.06 (m, 1H), 2.53 (m, 2H), 1.53 (s, 9H)ppm; ESI mass spectrum 516(M+H, 100 free base); HRMS calcd. for C22 H23 BrN5 O5 516.088255, found 516.086811 (free base).
EXAMPLE 536 N2 -(2,5-Dimethyl-4-chlorobenzenesulfonyl)-N3 -[3-(4-amidinophenyl)isoxazolin-5(R,S)-ylacetyl]-(S)-2,3-diaminopropionic Acid TFA Salt
Prepared according to Example 490a. MS (ESI, e/z, relative intensity): 536 (M+H)+, (100%).
EXAMPLE 540 N2 -methylphenylcarbonyl-N3 -[3-(4-amidinophenyl)isoxazolin-5-(R,S)-ylacetyl]-(S)-2,3-diaminopropionic Acid
Obtained as colorless crystals, M.P. 166-168° C.; 1 H NMR (DMSO d6) δ: 9.38 (b, 2H), 9.18 (b, 2H), 8.42 (t, 1H), 8.20 (m, 1H), 7.21 (d, J=10.2 Hz, 4H), 5.00 (m, 1H), 4.50 (m, 1H), 3.30-3.73 (m. 3H), 2.58-2.65 (dd, 1H), 2.41-2.50 (dd, 1H), 2.34 (s, 3H)ppm; ESI mass spectrum 452(M+H, 100 free base); HRMS calcd for C23 H26 N5 O5 452.193394, found 452.1922251(free base).
EXAMPLE 540a N2 -methylphenylsulfonyl-N3 -[3-(4-amidinophenyl)isoxazolin-5-(R,S)-ylacetyl]-(S)-2,3-diaminopropionic Acid
Obtained as colorless crystals M.P. 136-138° C.; 1 H NMR (DMSO d6) δ: 9.39 (b, 2H), 9.27 (s, 2H), 8.18 (m, 2H), 7.80 (d, J=7.7 Hz, 1H), 7.44(t, 1H), 7.32(q, 2H), 4.96 (m, 1H), 3.90 (b, 1H), 3.81 (q, 1H), 3.40-3.60 (m, 2H), 3.04 (m, 2H), 2.60 (s, 2H), 2.24 (dd, J=7.7 and 15.6 Hz)ppm; ESI mass spectrum 488(M+H, 100 free base). HRMS calcd for. C22 H25 N5 SO6 488.160381, found 488.16292 (free base).
EXAMPLE 548 Preparation of 3-bromothiophene-2-sulfonyl Chloride
A solution of chlorosulfonic acid (14.3 g, 0.12 mol) in 35 mL of 1,2-dichloroethane was chilled to -10° C. and protected from moisture. Phosphorus pentachloride (20.8 g, 0.1 mol) was added in small portions while maintaining the temperature between -5° and -10° C. The resulting slurry was stirred at -10° C. for 30 minutes. Then, 3-bromothiophene (16.3 g, 0.1 mol) was added dropwise over a period of 45 minutes, maintaining the temperature between -5° and +5° C. During the addition of the 3-bromothiophene, hydrogen chloride gas was evolved; the reaction mixture became thick and pasty, and difficult to stir. Upon complete addition of the 3-bromothiophene, the reaction temperature was held at 0° C. for two hours. The reaction was then heated to 80° C. and kept there for one hour; during which the solids dissolved, and hydrogen chloride gas was evolved once more. The reaction mixture was chilled in an ice bath, poured over 250 g crushed ice, and stirred for one hour as the ice melted. The resulting two phase system was separated and the aqueous layer washed three times with 125 mL of chloroform. The combined organic phases were dried over anhydrous MgSO4, filtered, and concentrated in vacuo to give 24.1 g (92%) of crude product as a dark amber oil; 1 H NMR (300 MHz, CDCl3) δ 7.22 (d, J=5.3, 1H), 7.73 (d, J=5.3, 1H); Mass Spectrum (CH4 -DCI/GC-MS, e/z, relative abundance) 262.8, (M+H)+, 100%; 226.9, (M+H-HCl)+, 89.7%.
EXAMPLE 587A N2 -3-methylphenylsulfonyl-N3 -[3-(4-amidinophenyl)isoxazolin-5S-ylacetyl]-S-2,3-diaminopropionic Acid
The compound of Example 473C, Part B (0.077 g, 0.14 mmol) was dissolved in MeOH (4 ml), LiOH (0.0066 g, 0.158 mmol) in H2 O (4 ml) was added and the reaction mixture left to stir overnight. After evaporation of methanol the product precipitated from the aqueous as a white solid (0.027 g, 35% yield). HRMS calc'd for C22 H25 N5 O6 S: 488.160381 found: 488.160827.
EXAMPLE 602 Methyl N2 -n-butyloxycarbonyl-N3 -[3-(4-guanidinophenyl)isoxazolin-5-(R,S)-ylacetyl]-(S)-2,3-diaminopropionate, Trifluoroacetic Acid Salt
Part A: [3-[(4-t-butyloxycarbonylamino)phenyl]-isoxazolin-5-yl]acetic acid: This compound was prepared in 49% yield from 4-t-butyloxycarbonylaminobenzaldoxime and t-butyl vinyl acetate using the procedure described above for Ex. 275, Part A. 1 HNMR(CDCl3) δ 0.99 (t, 3H), 1.35 (m, 2H), 1.50 (s, 9H), 1.61 (m, 2H), 2.60 (dd, J=7.7 and 16.5 Hz, 1H) 2.84 (dd, J=5.9 & 16 Hz, 1H), 3.06 (dd, J=7.4 & 16.9 Hz, 1H), 3.48 (dd, J=10.3 & 16.5 Hz, 1H), 4.10 (t, 2H), 5.03 (m, 1H), 6.60 (broad s, 1H), 7.38 (d, J=8.4 Hz, 2H), 7.58 (J=8.3 Hz, 2H); IR(KBr): 2966, 1734, 1740, 1610, 1578, 1528, 1508, 1458, 1442, 1412, 1392, 1368 1234, 1160, 1058, 916, 878, 828, 772, 612 cm-1 ; HRMS calcd. for C20 H28 N2 O5 : 377.207647, Found 377.207278. Standard LiOH saponification conditions then afforded the corresponding carboxylic acid compound as colorless crystals in 88% yield. mp 178-180° C.; 1 HNMR(CDCl3) δ 1.52 (s, 9H), 2.67 (dd, J=7.8 and 16 Hz, 1H), 2.89 (dd, J=8.3 & 16 Hz, 1H), 3.06 (dd, J=9.5 & 16.9 Hz, 1H), 3.48 (dd, J=10.3 & 16.5 z, 1H), 5.03(m, 1H).
Part B: Methyl N2 -n-butyloxycarbonyl-N3 -[3-[(4-t-butyloxycarbonylamino)phenyl]isoxazolin-5-yl acetyl]-(S)-2,3-diaminopropionate: The compound of Example 602, Part A was condensed with methyl N2 -tBoc-(S)-2,3-diaminopropionate using the procedure described for Ex. 275, Part C above to provide the desired product. mp 80-82° C.; 1 HNMR(CDCl3) δ 1.88 (t,3H), 1.30 (m,2H), 1.47 (sm, 20H), 2.50 (dd, 1H), 2.61 (dd, 1H), 3.07 (dd, 1H), 3.40 (dd, 1H), 3.63 (t, 2H), 3.74 (s, 3H), 4.00 (m, 2H), 4.38 (m, 1H), 5.00 (m, 1H), 5.88 (dd, 1H), 6.77 (t, 1H), 7.58 (d, 2H), 7.84 (d, 2H), 10.4 (s, 1H), 11.6 (s, 1H); IR(KBr):3286, 2964, 1722, 1646, 1546, 1414, 1368, 1340, 1312, 1294, 1240, 1156, 1122, 1100, 1058, 1030, 844, 776 cm-1. Mass spectrum (CI/NH4) 663 (M+H, 20),563(7), 549(78), 506(81),463(100).
Part C: Methyl N2 -n-butyloxycarbonyl-N3 -(3-(4-quanidinophenyl)isoxazolin-5-yl acetyl]-(S)-2,3-diaminopropionate: The compound of Ex 602, part B was treated with TFA in dichloromethane to afford the corresponding aniline as its TFA salt. This intermediate was converted to the corresponding bis-BOC protected quanidino compound in 59% yield using the method of Kim et al. (Tet. Lett. 1993, 48, 7677). Deprotection under standard conditions (TFA/CH2 Cl2) provided the title compound as its TFA salt (90%). 1 HNMR(DMSO-d6) δ 1.89 (t, 3H), 1.34 (m, 2H), 1.57 (m, 2H), 2.44 (dd, 1H), 2.58 (t, 2H), 2.64 (m, 1H), 3.17 (m, 1H), 3.40 (m,2H), 3.65 (m, 1H), 3.70 (s, 3H), 4.00 (t, 2H), 4.31 (m, 1H), 5.02 (m, 1H), 6.80 (m, 1H), 7.28 (d, 2H), 7.64 (broads, 3H), 7.68 (d, 2H), 7.84 (broad, 1H) ; Mass spectrum(ES) m/z 463 (M+H, 100).
EXAMPLE 606 Methyl N2 -p-toluylsulfonyl-N3 -[3-(4-quanidinophenyl)isoxazolin-5-(R,S)-ylacetyl]-(S)-2,3-diaminopropionic Acid TFA Salt
Part A: The methyl di-Boc-quanidino-α-toluyl ester was prepared according to the procedure for example 602. Deprotection of the Boc-protecting groups then afforded example 606 as the TFA salt. 1 HNMR (DMSO) δ: 8.30 (dd, 2H), 8.09 (m, 1H), 7.68 (d, J=8.2 Hz, 2H), 7.60 (d, J=8.0 Hz, 2H), 7.35 (d, J=8.2 Hz, 2H), 7.28 (d, J=8.4 Hz, 2H), 4.88 (m, 1H), 4.00 (m, 1H), 3.42 (dt, 1H), 3.38 ((d, 3H), 3.05-3.33 (m, 3H), 2.40 (m, 1H), 2.36 (s, 3H), 2.25 (m, 1H) ppm; HR MS calcd. for C23 H29 N6 O6 S 517.186930; Found 517.186911.
Part B: Lithium hydroxide saponification on the product of part A then afforded example 605 in 39% yield after recrystallization from dichloromethane and ether. 1HNMR (CD3 OD) δ: 8.29(brd, S, 2H), 8.05 (brd, s, 1H), 7.75 (d, J=8.1 Hz, 2H), 7.70 (d, J=8.4 Hz, 2H), 7.31 (d, 4H), 5.02 (m, 1H), 3.85 (m, 1H), 3.60 (m, 2H), 3.41 (m, 1H), 3.20 (m, 1H), 2.64 (dd, 1H), 2.43 (dd, 1H), 2.40 (s, 3H);HR MS calcd. for C22 H27 N6 O6 S 503.171280; Found 503.170531.
EXAMPLE 625 N2 -p-methylphenylsulfonyl-N3 -[3- (4-amidinophenylmethyl)-isoxazolin-5-(R,S)-ylacetyl]-(S)-2,3-diaminopropionic Acid TFA Salt
Part A: 1-β-nitroethene-4-benzonitrile (Bourgvignon, J.et al., Can, J. Chem., 1985, 63, 2354) (0.9 g, 5.17 mmol) was reduced according to the method of Nakamura, et al. (Chem. Lett., 1985, 523) to afford 0.73 g (80%) of desired product. 1 H NMR (CDCl3) δ: 7.73 (d, J=8.42 Hz, 2H), 7.43 (d, J=8.42 Hz, 2H), 4.75 (d, J=6.96 Hz, 2H), 3.48 (d, J=6.96 Hz, 2H) ppm; Mass Spectrum (CH4 -CI) m/z (M+H)+ 177 (100%).
Part B: 1-β-nitroethane-4-benzonitrile (1.38 g, 7.8 mmol) was condensed with tert-butyl acrylate (1.4 ml, 9.4 mmol) according to the method of Curran, D. P., et al (J. Org. Chem., 1988, 53, 5369) to afford the crude ester. The ester was difficult to purify so the ester was hydrolyzed in 30 ml of 30% TFA/CH2 Cl2 for 48 h. The crude acid was extracted into aqueous NaHCO3. The aqueous layer was acidified and extracted with CH2 Cl2 and dried (MgSO4) to afford 1.48 g (80%) orange solid. 1 H NMR (CDCl3) δ: 7.97 (brd, 1H), 7.64 (d, J=8.42 Hz, 2H), 7.36 (d, J=8.42 Hz, 2H), 5.07 (dd, J=6.59,10.98 Hz, 1H), 3.79 (s, 2H), 3.20 (m,. 2H) ppm.
Part C: The product of Part B (366 mg, 1.6 mmol) was coupled with methyl-L-N.sup.α -p-toluylsulfonyl-2,3-diaminoproprionate using procedure described in Example 43D. Chromatography on silica gel (2%MeOH/CH2 Cl2) afforded 388 mg (50%).mp 141-144° C; 1 H NMR (CDCl3) δ: 7.75-7.65 (m, 2H), 7.60 (d, 2H), 7.45 (d, 2H), 7.30 (dd, 2H), 7.20 (m, 1H), 5.50 (dd, 1H), 4.99 (m, 1H), 4.20-3.99 (m, 1H), 3.90-3.70 (m, 3H), 3.55 (s, 3H), 3.30 (m, 3H), 2.42 (s, 3H) ppm; Mass Spectrum (NH3 -CI) m/z (M+H)+ 485.2 (100%); IR (KBr) 3276, 1738, 1666, 1538, 1338, 1162, 862, 822 cm-1.
Part D: The product of Part C (360 mg, 0.74 mmol) was subjected to the Pinner reaction previously described. Chromatography on silica gel (5-15% MeOH/CH2 Cl2) afforded 313 mg (75%) .mp 133-137° C.; 1 H NMR (DMSO-d6) δ: 9.20 (brd, 2H), 8.26 (t, J=5.86 Hz, 1H), 7.80 (d, J=8.06 Hz, 2H), 7.63 (d, J=8.06 Hz, 2H), 7.51 (d, J=8.06 Hz, 2H), 7.38 (d, J=8.06 Hz, 2H), 4.87-4.73 (m, 1H), 3.98-3.89 (m, 1H), 3.80 (s, 2H), 3.34 (s, 3H), 3.34-3.31 (m, 3H), 3.28 (m, 2H), 2.98 (dd, J=6.23, 17.21 Hz, 1H), 2.37 (s, 3H) ppm; Mass Spectrum (ESI) m/z (M+H)+ 502.2 (100%).
Part E: To the product of Part D (182 mg, 0.338 mmol) was added 1 ml MeOH, followed by lithium hydroxide (31 mg, 0.74 mmol). The mix ture was stirred for 18 h and the solvent was removed in vacuo and water added. HCl was added until a precipitate formed. The solid was filtered off and stirred in 2 ml HCl for 1 h. The acid was removed in vacuo to afford 72 mg of product which contained 15% methyl ester. Purification via standard HPLC techniques then afforded the desire product. 1 H NMR (DMSO-d6) δ: 9.35 (s, 2H), 9.08 (s, 2H), 8.14-8.07 (m, 2H), 7.78 (d, J=7.32 Hz, 2H), 7.66 (dd, J=2.19, 8.42 Hz, 2H), 7.51 (d, J=7.69 Hz, 2H), 7.36 (d, J=8.42 Hz, 2H), 4.86-4.69 (m, 1H), 3.92-3.80 (m, 1H), 3.79 (s, 2H), 3.30-2.90 (m, 4H), 2.49 (s, 3H) ppm; Mass Spectrum (ESI) m/z (M+H)+488.3 (100%).
EXAMPLE 651 Methy N2 -benzyloxycarbonyl-N3 -methyl-N3 -[3-(4-amidinophenyl)isoxazolin-5-(R,S)-ylacetyl]-(S)-2,3-diaminopropionate, Trifluoroacetic Acid Salt
Part A. Preparation of methyl N2 -benzyloxycarbonyl-N3 -methyl-[3-(4-N-Boc-amidinophenyl)isoxazolin-5-(R,S)-ylacetyl]-(S)-2,3-diaminopropionate.
To a mixture of 3-(4-N-Boc-amidinophenyl)-isoxazolin-5-ylacetic acid (prepared according to the procedure of Example 434, part F; 189 mg, 0.54 mmol), methyl N3 -methyl-N2 -Cbz-L-2,3-diaminopropionate (prepared according to Sakai and Ohfune, J. Am. Chem. Soc. 114, 998 (1992); 145 mg, 0.54 mmol) and TBTU (175 mg, 0.54 mmol) in ethyl acetate (10 mL) was added triethylamine (0.15 mL, 1.09 mmol). After stirring for 26 h, the mixture was diluted with ethyl acetate, washed with pH 4 buffer, then with saturated aqueous sodium bicarbonate, then with saturated brine. The organic phase was dried (MgSO4) and concentrated. The residue was flash chromatographed (ethyl acetate) to provide the product as a colorless glass (279 mg, 86%): NMR (CDCl3) δ 7.88 (m, 2H), 7.69 (m, 2H), 5.79 (bd, 1H), 5.09 (m, 3H), 4.58 (m, 1H), 3.86 (m, 1H), 3.77 (2s, 3H), 3.63 (m, 2H), 3.14 (dd, 1H), 3.01 (2s, 3H), 2.9 (m, 1H), 2.53 (m, 1H), 1.66 (b, 2H), 1.56 (s, 9H); mass spec (ESI) m/z 596.2 (M+H+, 100%).
Part B. Preparation of Methyl N2 -benzyloxycarbonyl-N3 -methyl-N3 -[3-(4-amidinophenyl)isoxazolin-5-(R,S)-ylacetyl]-(S)-2,3-diaminopropionate, trifluoroacetic acid salt
The product of part A (226 mg, 0.38 mmol) was dissolved in dichloromethane (3 mL) and treated with trifluoroacetic acid (1 mL). After stirring at room temperature for 4 h, the mixture was diluted with ether and stirred. The resulting white solid was collected by filtration to provide the title product as a white solid (201 mg, 87%): NMR (DMSO-d6) δ 9.39 (bs, 2H), 9.19 (bs, 2H), 7.87 (s, 4H), 7.79 (t, 1H), 7.32 (m, 5H), 5.03 (3H), 4.40 (m, 2H), 3.90 (m, 1H), 3.65 (2s, 3H), 2.95 and 2.82 (4s, 3H), 3.6-2.8 (4H); mass spec (ESI) m/z 496.3 (M+H+, 100%).
EXAMPLE 666 N2 -(methyl)-N2 -m-toluylsulfonyl-N3 [-3-(4-amidinophenyl)-isoxazoline-5-(R,S)-ylacetyl]-(S)-2,3-diaminopropionic Acid TFA Salt
Part A: Methyl N3 -[3-(4-cyanophenyl)isoxazolin-5-(R,S)-ylacetyl]-N2 -m-toluyl-(S)-2,3-diaminopropionate obtained as the precursor to Example 300 was subjected to a selective Mitsonubo-N-methylation of the sulfonamide (Acta. chem. scand. 1994, 48, 324333),to afford methyl N2 -(methyl)-N2 -m-toluyl-N3 -[3-(4-cyanophenyl)isoaxzolin-5-(R,S)-ylacetyl]-(S)-2,3-diaminopropionate as colorless crystals. M.P=148-149° C. 1 HNMR(CDCl3) δ: 7.77 (d, 2H), 7.60 (m, 2H), 7.46 (m, 2H), 7.41 (d, 2H), 6.07 (t, 1H), 5.21 (m, 1H), 4.80 (dd, J=4.8 & 10.6 Hz, 1H), 3.81 (m, 1H), 3.56 (s, 3H), 3.43 (m, 2H), 3.25 (dd, J=7.4 & 17.4 Hz, 1H), 2.80 (dd, J=8 & 17.1 Hz, 1H), 2.77 (s, 3H), 2.56 (dd, J=7.7 & 15.1 Hz, 1H), 2.44 (s, 1H) ppm; IR (KBr) 3340, 2224, 1726, 1644, 1610, 1596, 1534, 1440, 1414, 1402, 1366, 1336, 1284, 1258, 1212, 1144, 1012, 934, 918, 896, 844, 812, 784, 690, cm-1. ESI mass spectrum 499 (M+H, 48), 359(63), 279(53), 198(100). HR MS calcd. for C24 H27 N4 O6 S 499.165132 found 499.164946.
Part B: The cyano procursor from part A was then subjected to the Pinner amidine reaction conditions as per example 275E to obtain the desired compound as the methyl ester in 60% overall yield. Saponification with 6N HCl followed by HPLC purification [solvent A: CH3 CN: H2 O: TFA/2%:98%:0.05%, solvent B: CH3 CN:H2 O:TFA/80%:20%:0.05%] afforded the desired amidine acid compound 666 as its TFA salt. 1 HNMR (CDCl3) δ: 9.35 (s, 1H), 9.23 (s, 1H), 8.20 (brd, 2H), 7.89 (brd, 4H), 7.57 (d, J=8 Hz, 2H), 7.40 (d, J=8 Hz, 2H), 5.05 (m, 1H), 4.67 (m, 1H), 3.50-3.66 (m, 3H), 3.20-3.40 (m, 2H), 2.80 (s, 3H), 2.55 (m, 1H), 2.35 (m/s, 4H) ppm; ESI mass spectrum 502(M+H, 100), HRMS calcd for C23 H27 N5 SO6 502.176031 found 502.176612.
EXAMPLE 703 Methyl N2 -n-butyloxycarbonyl-N3 -[3-(4-amidinophenyl)isoxazol-5-yl acetyl]-L-2,3-diaminopropionate TFA Salt
Part A. Preparation of Methyl 3-(4-cyanophenyl)isoxazo-5-yl acetate
To a suspension of methyl 3-(4-cyanophenyl)-(5R,S)-isoxazolin-5-yl acetate (5.28 g, 21.62 mmol) in chloroform (150 mL) were added N-bromosuccinimide (4.23 g, 23.78 mmol) and AIBN (100 mg) and the mixture was refluxed. Small amounts of AIBN (100 mg-200 mg) were added at one hour intervals until TLC showed a complete reaction. Potassium acetate (17.3 g) and acetic acid (6.5 mL) were added and the reaction mixture was refluxed for 1 hour, cooled, then poured into lN NaOH (325 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (3×100 mL). The organic layers were combined and washed with sat. NaCl, dried over Na2 SO4, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel (15% to 35% EtOAc in Hexane) to yield 2.2 g (42%) of an off-white solid as product; 1 H NMR (300 MHz, CDCl3) δ: 7.93 (dd, 2H), 7.76 (dd, 2H), 6.67 (s, 1H), 3.92 (s, 2H), 3.8 (s, 3H).
Part B. Preparation of Methyl 3-(4-methoxyiminophenyl)isoxazo-5-yl acetate HCl salt.
A suspension of methyl 3-(4-cyanophenyl)isoxazo-5-yl acetate (2.19 g, 9.04 mmol) in 100 mL of anhydrous methanol was chilled in an ice bath and dry HCl gas was bubbled through the reaction mixture until a solution was obtained. The total addition time was two hours. The reaction flask was sealed and the reaction mixture was allowed to warm to room temperature, with stirring, over a period of about 24 hrs. At this point, the methanolic solution was poured into 500 mL of anhydrous ether, precipitating the product, and the resulting slurry was chilled to -25° C. for 3 hours. The precipitate was filtered, washed with two 100 mL portions of chilled anhydrous ether, and suction dried under nitrogen to afford 2.3 g (82%) of the hydrochloride salt; 1 H NMR (300 MHz, suspension in CDCl3) δ 8.52 (d, J=8.06 Hz, 2H), 8.03 (d, J=8.4 Hz, 2H), 6.67 (s, 1H), 4.6 (s, 3H), 3.93 (s, 2H), 3.8 (s, 3H).
Part C. Preparation of Methyl 3-(4-amidinophenyl)isoxazo-5-yl acetate HCl salt.
A solution of methyl 3-(4-methoxyiminophenyl)isoxazo-5-yl acetate HCl salt (2.3 g, 7.4 mmol) in 50 mL of anhydrous methanol was chilled in an ice bath and 2M ammonia in methanol (18.5 mL, 37 mmol) was added. The reaction flask was sealed and the reaction mixture was allowed to warm to room temperature, with stirring, over a period of 24 hrs. The amber solution was then concentrated in vacuo to give 2.2 g (quant. yield) of a yellow foam; 1 H NMR (300 MHz, d6 -DMSO) δ 9.6-9.2 (b), 8.12 (d, J=8.4 Hz, 2H), 7.97 (d, J=8.4 Hz, 2H), 7.14 (s, 1H), 4.15 (s, 2H), 3.7 (s, 3H).
Part D. Preparation of Methyl 3-(4-N-Boc-amidinophenyl)isoxazo-5-yl acetate.
To a solution of methyl 3-(4-amidinophenyl)isoxazo-5-yl acetate HCl salt (2.2 g, 7.4 mmol) in 30 mL DMF cooled with an ice bath was added triethylamine (2.06 mL, 14.8 mmol) and di-tert-butyl dicarbonate (1.78 g, 8.14 mmol). The reaction mixture was warmed to room temperature and stirred for 64 hrs. The reaction mixture was then partitioned between EtOAc and water. The aqueous layer was washed with EtOAc. The organic layers were combined and washed with water, sat. NaCl, dried over Na2 SO4, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel (15% to 25% EtOAc in Hexane) to afford 1.45 g (54%) of product; 1 H NMR (300 MHz, CDCl3) δ 7.96 (d, J=8.4 Hz, 2H), 7.87 (d, J=8.4 Hz, 2H), 6.65 (s, 1H), 3.91 (s, 2H), 3.8 (s, 3H), 1.56 (s, 9H).
Part E. Preparation of 3-(4-N-Boc-amidinophenyl)isoxazo-5-yl acetic acid.
To a solution of methyl 3-(4-N-Boc-amidinophenyl)isoxazo-5-yl acetate (1.45 g, 4.03 mmol) in 30 mL of methanol was added a solution of lithium hydroxide monohydrate (0.195 g, 4.64 mmol) in water (5 mL). The mixture was stirred at room temperature for 16 hours. The reaction mixture was then concentrated in vacuo and the residue was diluted with water and the resulting mixture was cooled using an ice bath. 1N HCl was slowly added to a pH of 3-4 and the resulting acidic aqueous mixture was extracted repeatedly with EtOAc. The organic layers were combined and washed with sat. NaCl, dried over Na2 SO4, filtered and concentrated in vacuo to yield 0.97 g (70%) of an off-white powdery solid as product; 1 H NMR (300 MHz, d6 -DMSO) δ 8.07 (d, J=8.79 Hz, 2H), 7.97 (d, J=8.4 Hz, 2H), 7.03 (s, 1H), 3.99 (s, 2H), 1.45 (s, 9H).
Part F. Preparation of Methyl N2 -n-butyloxycarbonyl-N3 -[3-(4-N-Boc-amidinophenyl)isoxazo-5-yl acetyl]-L-2,3-diaminopropionate.
To a solution of 3-(4-N-Boc-amidinophenyl)isoxazo-5-yl acetic acid (0.262 g, 0.76 mmol), methyl N2 -n-butyloxycarbonyl-L-2,3-diaminopropionate HCl salt (0.193 g, 0.76 mmol), and TBTU (0.256 g, 0.8 mmol) in DMF (15 mL) was added triethylamine (0.45 mL, 3.23 mmol) and the resulting reaction mixture was allowed to stir at room temperature for 16 hours. The reaction mixture was partitioned between EtOAc and water. The water layer was washed twice with EtOAc. The organic layers were combined and washed with water, pH 4 buffer, 5% NaHCO3, and sat. NaCl, dried over Na2 SO4, filtered, and evaporated in vacuo. The residue was chromatographed on silica gel (100% EtOAc) to yield 0.315 g (76%) of a slightly amber foam; 1 H NMR (300 MHz, CDCl3) δ 7.93 (d, J=8.42 Hz, 2H), 7.83 (d, J=8.42 Hz, 2H), 6.6 (s, 1H), 6.57 (bm, 1H), 5.66 (bm, 1H), 4.45 (bm, 1H), 4.05 (m, 2H), 3.77 (s, 5H), 3.7 (m, 2H), 1.57 (s, 9H), 1.56 (m, 2H), 1.35 (m, 2H), 0.9 (t, J=7.32 Hz, 3H).
Part G. Preparation of Methyl N2 -n-butyloxycarbonyl-N3 -[3-(4-amidinophenyl)isoxazo-5-yl acetyl]-L-2,3-diaminopropionate TFA salt.
A solution of methyl N2 -n-butyloxycarbonyl-N3 -[3-(4-N-Boc-amidinophenyl)isoxazo-5-yl acetyl]-L-2,3-diaminopropionate (0.215 g, 0.39 mmol) in 1:1 methylene chloride/trifluoroacetic acid (20 mL total) was stirred at room temperature for 16 hours. The reaction mixture was then concentrated in vacuo and the residue chromatographed on silica gel (10% to 30% methanol in chloroform) to yield 0.11 g (50%) of a white solid; 1 H NMR (300 MHz, d6 -DMSO) δ 9.4 (bs, 2H), 9.15 (bs, 2H), 8.45 (t, 1H), 8.11 (d, J=8.42 Hz, 2H), 7.94 (d, J=8.42 Hz, 2H), 7.53 (d, J=8.06 Hz, 1H), 7.01 (s, 1H), 4.21 (m, 1H), 3.95 (t, 2H), 3.81 (s, 2H), 3.62 (s, 3H), 3.55 (m, 1H), 3.34 (m, 1H), 1.5 (m, 2H), 1.3 (m, 2H), 0.87 (t, J=7.32 Hz, 3H).; Mass Spectrum (ESI, e/z, relative abundance) 446.3, (M+H)+, 100%.
EXAMPLE 717 N2 -Phenylmethylsulfonyl-N3 -[3-(4-amidinophenyl)isoxazolin-5(R,S)-ylacetyl]-(S)-2,3-diaminopropionic Acid TFA Salt
Prepared according to Example 490a. MS (ESI, e/z, relative intensity): 488 (M+H)+, (100%).
EXAMPLE 816 N2 -p-toluylsulfonyl-N3 -[5-(4-amidinophenyl)isoxazolin-3-(R,S)-yl-acetyl]-(S)-2,3-diaminopropionic Acid TFA Salt
The title compound was prepared in a manner similar to example 829. Saponification of the methyl ester via standard techniques then afforded crude compound 816, which was purified via HPLC [graduant flow, solvent A CH3 CN(2%):H2 O(98%):TFA(0.05%), solvent B: CH3 CN(80%):H2 O(20%):TFA(0.05%),] to afford colorless crystals of compound 816 as its TFA salt. 1 HNMR(CDCl3) δ:
9.30 (brds, 4H), 8.34 (t, 1H), 8.12 (d,J=9.2 Hz, 1H), 7.81 (d, J=8.3 Hz, 1H), 7.60 (d, J=8.0 Hz, 1H), 5.60 (dt, 1H), 3.81 (q, 1H), 3.43 (dt, 1H), 3.25 (m, 1H), 3.20 (d, 1H), 3.03 (m, 1H), 2.89 (m, 1H), 2.50 (s, 1H), 2.34(s,3H) ppm; ESI mass spectrum 488 (M+H,100), HRMS calcd. for C22 H26 N5 O6 S 488.160381; found 488.158785.
EXAMPLE 829 Methyl N2 -n-butyloxycarbonyl-N3 -[5-(4-amidinophenyl)isoxazolin-3-yl acetyl]-(2S)-2,3-diaminopropionate
Part A: t-Butyl [5-(4-cyanophenyl)isoxazolin-3-yl]acetate:
Cycloaddition of 4-cyanophenylethylene (MP & D chemical Co.) and tert-butyl-3-oxopropionate oxime was carried out following the procedure of Gree et. al. (Bioorganic & Medicinal Chemistry letters 1994, 253) to provide the desired isoxazoline in 72% yield. 1 HNMR(CDCl3) δ: 1.40 (s, 9H), 3.00 (dd, J=8.3 and 17 Hz, 1H), 3.35 (dd(AB) J=18 and 8.3 Hz, 2H),3.48 (m, 1H), 5.60 (dd, J=9 and 4.5 Hz, 1H), 7.47 (d, J=8 Hz, 2H), 7.65 (d, J=8 Hz, 2H); IR 2235, 1718, 1610 cm-1. Mass spectrum m/z 287(M+H, 100).
Part B: [5-(4-cyanophenyl)isoxazolin-3-yl]acetic acid:
Hydrolysis of the compound of Ex.829, Part A with excess TFA in dichloromethane afforded the acid in 90% yield. 1 HNMR (CDCl3) δ 3.00 (dd, J=8 and 17.2 Hz, 1H), 3.55 (s, 2H), 3.59 (m, 1H), 5.66 (dd, J=8 and 11 Hz, 1H), 7.45 (d, J=8.4 Hz, 2H), 7.66 (d, J=8.0 Hz, 2H); IR(KBr) 3325, 2235, 1718, 1605 cm-1 ; Mass spectrum m/z 231 (M+H, 100).
Part C: Methyl [5- (4-Boc-amidinophenyl)isoxazolin-3-yl]Acetate:
The compound of Ex. 829, Part B compound was then subjected to the standard Pinner reaction conditions described in Ex. 275, Part D to afford an amidino compound, which, without purification, was subjected to treatment with di-tert-butyldicarbonate in dioxane/water (9:1) and excess triethylamine to afford the desired compound in 28% yield. 1 HNMR(CDCl3) δ 1.54 (s,9H), 2.98 (dd, J=8 and 17 HZ, 1H), 3.49 (s, 2H), 3.53 (m, 1H), 3.71 (s, 3H), 5.63 (dd, J=8 & 11.4 Hz, 1H), 7.38 (d, 8.2 Hz, 2H), 7.82 ((d, 8.2 Hz, 2H); Mass spectrum m/z 362(M+H, 8), 306(18), 262(M+H-Boc, 100).
Part D: [5-(4-Boc-amidinophenyl)isoxazolin-3-yl]acetic acid:
Hydrolysis of the ester using standard LiOH conditions afforded the desired acid in 5% yield. 1 HNMR(CDCl3) δ 1.54 (s,9H), 3.00 (dd, J=8 and 17 HZ, 1H), 3.51 (s, 2H), 3.53 (m, 1H), 5.63 (dd, J=8 & 11.4 Hz, 1H), 7.38 (d, 8.2 Hz, 2H), 7.82 ((d, 8.2 Hz, 2H); Mass spectrum m/z 348(M+H,12),248(M+H-Boc, 100).
Part E: Methyl N2 -n-butyloxycarbonyl-N3 -[5-(4-amidinophenyl)isoxazolin-3-yl-acetyl](S)-2,3-diaminopropionate, trifluoroacetate:
The compound of Ex. 829, Part D was coupled with methyl-(S)-N2 -n-butyloxycarbonyl-2,3-diaminopropionate following the procedure described in Ex. 275, Part C to give the Boc protected intermediate in 80% yield. 1 HNMR(CDCl3) δ 0.89 (t, 3H), 1.32 (m, 2H), 1.53 (s, 9H), 1.17 (m, 2H), 2.95 (dd, J=8 and 17 HZ, 1H), 3.33 (s, 2H), 3.46 (m, 1H), 3.60 (m, 2H), 3.73 (s, 3H), 4.00 (m, 2H), 4.31 (m, 1H), 5.60 (dd, J=8 & 11.4 Hz, 1H), 5.70 (bd, 1H), 6.70 (broad, 1H), 7.33 (d, 8.2 Hz, 2H), 7.89 ((d, 8.2 Hz, 2H); Mass spectrum m/z 534 (M+H, 30), 434 (M+H-Boc, 100). Deprotection by treatment of the above Boc-amidine with excess TFA in dichloromethane provided the title compound as the TFA salt. 1 HNMR(CDCl3 /DMSO-d6) δ 1.88 (t, 3H), 1.30 (m, 2H), 1.53 (m, 2H), 3.00 (dd, J=8 and 17 HZ, 1H), 3.32 (s, 2H), 3.40-3.63 (m, 3H), 3.63 (d, 3H), 3.98 (t, 2H), 4.29 (m, 1H), 5.60 (dd, J=8 & 11 Hz, 1H), 6.80 (d, 1H), 7.50 (d, J=8 Hz, 2H), 7.80 (d, J=8.2 Hz, 2H), 8.03 (broad s, 1H), 9.05 (broad s, 2H); IR(KBr): 3388, 1718, 1664, 1620, 1528, 1456, 1436, 1384, 1366, 1280, 1254, 1168, 1144, 1074, 980, 882, 778 cm-1 ; Mass spectrum(ES) m/z 448 (M+H, 100)
EXAMPLE 952 Methyl N2 -m-toluenesulfono-N3 -[3-(4-N-isopropylamidophenyl)isoxazolin-5R-ylacetyl]-S-2,3-diaminopropionate
Methyl N2 -m-toluenesulfono-N3 -[3-(4-cyanophenyl)isoxazolin-5R-ylacetyl]-S-2,3-diaminopropionate (prepared as in example 473 part C above) (0.098 g, 0.0002 mol) was stirred with isopropyl alcohol (0.018 ml, 0.0002 mol) and sulfuric acid (5 ml) for 12 hours. The reaction mixture was poured over ice and diluted to three times its' volume with water. The title compound was filtered as a pale brown solid. 1 H NMR (CDCl3) δ: 7.79-7.61 (m, 6H); 7.38-7.36 (m, 2H); 6.49-6.40 (m, 1H); 6.01-5.99 (m, 1H); 5.62-5.55 (m, 1H); 5.19-5.08(m, 1H); 4.31-4.28(m, 1H); 4.11-3.99(m, 1H); 3.56 (s, 3H); 3.72-3.48 (m, 4H); 3.24-3.16 (dd, 1H, J=7.3, 17.0); 2.41 (s, 3H); 1.29-1.27 (d, 6H, J=6.59 Hz). MS(ESI) calc'd for C26 H32 N4 SO7 545.3 found 545.2 (M+H)+
EXAMPLE 954 N2 -3-(n-butylcarbamoyl)-N3 -[3- (4-amidophenyl)isoxazolin-5R-ylacetyl]-S-2,3-diaminopropionic Acid
Following the procedure outlined for example 1945 above, Methyl N2 -3-(n-butylcarbamoyl)-N3 -[3-(4-cyanophenyl)isoxazolin-5R-ylacetyl]-S-2,3-diaminopropionate (0.87 g, 0.002 mol) gave a 66% yield of N2 -3-(n-butylcarbamoyl)-N3 -[3-(4-amidophenyl)isoxazolin-5R-ylacetyl]-S-2,3-diaminopropionic acid. 1 H NMR (CDCl3) δ: 12.7 (bs, 1H); 8.12-8.09 and 7.28-7.26 (2m, 1H); 8.05 and 7.43 (2s, 1H); 7.94-7.92 (d, 2H, J=8.54); 7.87 (s, 1H); 7.73-7.70 (d, 2H, J=8.5 Hz); 6.51-6.49 (m, 1H); 5.02-4.95 (m, 1H); 3.95-3.90 (m, 1H); 3.58-3.47 (m, 2H); 3.29-3.13 (m, 2H); 2.72-2.38 (m, 4H); 1.52-1.46 (m, 2H); 1.34-1.25 (m, 2H); 0.87-0.85 (t, 3H, J=4.3 Hz). MS(ESI): Cacl'd for C20H26N407 435.2 found 435.2 (M+H)+.
EXAMPLE 956 N2 -3-methylphenylsulfonyl-N3 -[3-(4-amidophenyl)-5R-ylacetyl]-S-2,3-diaminopropionic Acid
Part A: Methyl N2 -m-toluenesulfono-N3 -[3-(4-amidophenyl)-5S-ylacetyl]-S-2,3-diaminopropionate hydrochloride.
Methyl N2 -m-toluenesulfono-N3 -[3-(4-cyanophenyl)-5R-ylacetyl]-S-2,3-diaminopropionate (0.19 g, 0.00039 mol) was dissolved in 10 ml concentrated sulfuric acid. After stirring for 12 hours the reaction mixture was poured over 10 g of ice and 20 ml of water was added. The white solid was filtered, washed once with water and dried under vacuum overnight to give methyl-N2 -m-toluenesulfono-N3 -[3-(4-amidophenyl)-5S-ylacetyl]-S-2,3-diaminopropionate as a white powder. IR(neat) cm-1 : 3404, 3340, 3274, 3202, 2930, 1710, 1652, 1612, 1526, 1320, 1286, 1238, 1174, 1100, 1086, 1070, 886, 850, 614, 574. MS(ESI): calc'd for C23 H26 N4 O7 S 503.2 found 503.3(M+H)+.
Part B: N2 -m-toluenesulfono-N3 -[3-(4-amidophenyl)-5R-ylacetyl]-S-2,3-diaminopropionic acid
Methyl N2 -m-toluenesulfono-N3 -[3-(4-amidophenyl)-5R-ylacetyl]-S-2,3-diaminopropionate hydrochloride (0.146 g, 0.29 mmol) was dissolved in MeOH (5 ml), LiOH (0.013 g, 0.32 mmol) in H2 O (5 ml) was added and the reaction mixture left to stir overnight. Purification was done by HPLC on a Vyadek column using a gradient of 0.05%TFA/water to 0.05%TFA/acetonitrile over 45 min. The flow was set to 10 ml/min and the detector at 254 nm. The peak eluted at 25 min, the volatiles were evaporated in vacuo, and the solid dried under vacuum. MS(ESI) calc'd for C22 H24 N4 O7 S: 489.2 found: 489.2.
EXAMPLE 978 Methyl N2 -m-toluenesulfono-N3 -[3-(5-amidopyrid-2-yl)isoxazolin-5S-ylacetyl]-2,3-diaminopropionate
mp 192-195.5° C. (dec). 1 H NMR (DMSO-d6, 300 MHz) δ 2.28 (dd, J=14.6, 7.0 Hz, 1H), 2.36 (s, 3H), 2.44-2.54 (m, 1H, under DMSO), 3.04-3.15 (m, 1H), 3.20 (dd, J=17.6, 7.3 Hz, 1H), 3.30-3.40 (m, 1H, under water), 3.53 (dd, J=17.6, 10.6 Hz, 1H), 3.80-3.89 (m, 1H), 4.92-5.05 (m, 1H), 7.38-7.48 (m, 2H), 7.54-7.61 (m, 2H), 7.68 (br s, 1H), 7.98 (d, J=8.1 Hz, 1H), 8.04-8.10 (m, 2H), 8.23 (br s, 1H), 8.27 (dd, J=8.1, 2.2 Hz, 1H), 9.06 (d, J=1.5 Hz, 1H), 12.76 (br s, 1H). IR (KBr) 3388, 3314, 3274, 3186, 1712, 1662, 1584, 1546, 1418, 1344, 1160, 934, 794, 712, 688, 620, 576 cm-1. MS (ESI) 490 (M+H, 100).
EXAMPLE 979 N2 -[(p-ethyl)phenylsulfonyl]-N3 -[3-(4-carboxamidophenyl)isoxazolin-5-(R,S)-ylacetyl]-(S)-2,3-diaminopropionate
1 HNMR (DMSO) δ 8.12 (2H,m), 7.94 (2H, d, J=8.423 Hz), 7.74 (2H, m), 7.70 (2H, d, J=8.423 Hz), 7.46 (1H, s),7.40 (2H, m), 4.94 (1H, m), 3.92 (1H, m), 3.56 (2H, m), 3.37 (3H, m), 2.70 (2H, m), 2.45 (3H, m), 1.22 (3H, m) ppm; MS (ESI) m/z 503.3 (M+H)+.
EXAMPLE 996 N2 -o-toluenesulfonyl-N3 -[5-(4-amidinophenyl)isoxazolin-3(R,S)-ylformyl]-(S)-2,3-diaminopropionic Acid TFA Salt
Standard cycloaddition techniques using ethylchlorooximido acetate(Aldrich) and 4-cyanostyrene agfforded the desired precursor ethyl-5-(4-cyanophenyl)-isoxazoline carboxylate. Saponification followed by coupling with methyl N2 -o-toluylsulfonyl-(S)-2,3-diaminopropionate via standard techniques afforded the desired cyanoprecursor. Formation of the amidine via standard Pinner reaction conditions afforded the desired compound as colorless crystals after HPLC purification; M.P. 84-86° C.; 1 HNMR(DMSO d6) δ: 9.45 (b, 1H), 9.35 (b, 1H), 8.40 (q, 1H), 8.21 (dd, 1H), 7.81 (t,2H), 7.77 (d, J=8.5 Hz, 2H), 7.55 (d, J=8.5 Hz, 2H), 7.38-7.49 (t, 1H), 7.25 (m, 2H), 5.83 (m, 1H), 3.89 (q, 1H), 3.23-3.71 (m, 3H), 2.98(q, 1H), 2.57 (s,3H) ppm; ESI mass spectrum 474 (M=H, 100 free base); HRMS calcd for C21 H24 N5 O6 S 474.144731, found 474.143847.
EXAMPLE 1540 2-(n-Butyloxycarbonylamino)-3-[3-(4-amidinophenyl)-1-oxo-2,8-diazaspiro[4,5]dec-2-en-8-yl]propionic Acid Bis Trifluorqacetic Acid Salt
Part A: 3-(4-Cyanophenyl)-8-benzyloxycarbonyl-1-oxyo-2,8-diazaspiro[4,5]dec-2-ene.
The title material was prepared from 4-cyanobenzaldoxime (7.0 g, 48 mmol) and 1-benzyloxycarbonyl-4-methylenepiperidine (De Amici, M.; Fr.o slashed.lund, B.; Hjeds, H. Krogsgaard-Larsen, P. Eur. J. Med. Chem. 1991, 26, 625) (11.0 g, 48 mmol) as described in Example 4, Part B. The crude adduct was purified by flash chromatography using a gradient hexane/ethyl acetate solvent system, starting with hexane and progressing to 65% ethyl acetate/hexane in 5% increments to give 14.4 g (86%) of a pale yellow gum. 1 H NMR (DMSO-d6, 300 MHz) δ 7.75 (d, J=8 Hz, 2H), 7.69 (d, J=8 Hz, 2H), 7.37-7.29 (m, 5H), 5.15 (s, 2H), 3.95-3.83 (m, 2H), 3.51-3.44 (m, 2H), 3.09 (s, 2H), 2.00-1.89 (m, 2H), 1.83-1.70 (m, 2H). IR (KBr) 2228, 1698 cm-1. HRMS (DEP, NH3) Calc. for (M+H)+ : 376.1661. Found: 376.1646.
Part B: 3-(4-Amidinophenyl)-1-oxo-2,8-diazastiro[4.5]dec-2-ene dihydrochloric acid salt.
The intermediate of Part A (4.18 g, 11.1 nmol) was subjected to standard Pinner conditions to give a crude amidine-amine salt, which was purified by flash chromatography using a graduated solvent system starting with chloroform and progressing to 30% methanol in chloroform to give 1.8 g (48%) of the title compound. 1 H NMR (DMSO-d6, 300 MHz) δ 9.56 (br s, 1.5H), 9.36 (br s, 1.5H), 7.95 (d, J=8.7 Hz, 2H), 7.86 (d, J=8.4 Hz, 2H), 4.15-4.14 (m, 1H), 3.43 (s, 2H), 3.36 (s, 4H), 2.05-2.04 (m, 4H). HRMS (DEP, NH3) Calc. for (M+H)+ : 259.1559. Found: 259.1562.
Part C: Methyl 2-(R,S)-(benyloxycarbonylamino)-3-[3(4-amidinothenyl)-1-oxo-2,8-diazaspiro[4,5]dec-2-en-8-yl]-propionate dihydroiodic acid salt.
The intermediate of Part B (1.67 g, 5.0 mmol) was dissolved in dimethylformamide (20 mL) and sodium bicarbonate (1.27 g, 15.1 mmol) was added. A solution of N-benzyloxycarbonyl-3-iodo-L-alanine methyl ester (Marki, W.; Schwyzer, R. Helv. Chim. Acta 1975, 58, 1471) (2.0 g, 5.5 mmol) in dimethylformamide (6 mL) was added and the mixture was stirred at room temperature for 7 d. The solvent was evaporated and the residue was flash chromatographed using a graduated solvent system starting with chloroform and progressing to 20% methanol/chloroform in 5% steps to give 1.78 g of impure material. It was chromatographed a second time as above to give 1.72 g (45%) of pure material. 1 H NMR (DMSO-d6, 300 MHz) δ 9.16 (br s, 4H), 7.87 (s, 4H), 7.71 (d, J=7.7 Hz, 1H), 7.39-7.30 (m, 5H), 5.10-5.05 (m, 2H), 4.29-4.27 (m, 1H), 3.65 (s, 3H), 3.23 (s, 2H), 2.66-2.60 (m, 4H), 2.46 (m, 2H), 1.75 (m, 4H). IR (KBr) 3300-2950 (br), 1718, 1674 cm-1. HRMS (FAB, glycerol) Calc for (M+H)+ : 494.2403. Found: 494.2401.
Part D: Methyl 2-(R,S)-amino-3-[3-(4-amidinophenyl)-1-oxo-2,8-diazaspiro[4,5]dec-2-en-8-yl]propionate trihydrobromic acid salt.
The intermediate of Part C (1.2 g, 1.6 mol) was dissolved in 30% hydrogen bromide in acetic acid (10 mL) and the solution was stirred at room temperature for 17.5 h. The mixture was diluted with ether and filtered. The solid was washed with ether and dried to give 0.872 g (89%) of a gray solid. 1 H NMR (DMSO-d6 +TFA-d, 300 MHz) δ 9.43 (s, 2H), 9.14 (s, 2H), 7.94-7.85 (m, 4H), 4.84 (m, 1H), 3.84 (s, 4H), 3.55-3.42 (m, 6H), 2.16 (br m, 4H). MS (ESI) 360 (M+H).
Part E: Methyl 2-(n-butyloxycarbonylamino)-3-[3-(4-amidinophenyl)-1-oxo-2,8-diazaspiro[4.5]dec-2-en-8-yl]propionate hydrobromic acid salt.
n-Butylchloroformate (45 μL, 0.35 nmol) was added to a solution of the intermediate of Part D (0.200 g, 0.33 mmol) and triethylamine (0.14 mL, 1.0 mmol) in dimethylformamide (2 mL) and the mixture was stirred at room temperature for 2 h. The solution was flash chromatographed using a gradient solvent system starting with chloroform and progressing to 20% methanol/chloroform in 5% steps to give 0.249 g of the title compound. MS (ESI) 460 (M+H).
Part F: 2-(n-Butyloxycarbonylamino)-3-[3- (4-amidinophenyl)-1-oxo-2,8-diazaspiro[4,5]dec-2-en-8-yl]propionic acid bis trifluoroacetic acid salt.
The intermediate of Part E (229 mg, 0.33 mmol) was dissolved in methanol (7 mL) and water (7 mL) and lithium hydroxide hydrate (33 mg, 0.79 mmol). The mixture was stirred at room temperature for 24 h and additional lithium hydroxide hydrate (18 mg, 0.43 mmol) was added. The mixture was stirred for 24 h and the methanol was evaporated. The aqueous residue was diluted with trifluoroacetic acid (0.15 mL) and the mixture was purified by Prep HPLC as described in Example 514A, Part B to give 31 mg (11%) of the title compound. 1 H NMR (DMSO-d6, 300 MHz) δ 9.40 (br s, 2H), 9.12 (br s, 2H), 7.91-7.86 (m, 4H), 7.61 (br, 1H), 6.56 (br, 1H), 4.44 (br, 1H), 4.00 (t, J=6.2 Hz, 2H), 3.38 (m, 6H, under water peak), 2.03 (br, 4H), 1.58-1.54 (m, 2H), 1.36-1.34 (m, 2H), 0.90 (t, J=7.4 Hz, 3H). HRMS (FAB, glycerol) Calc. for (M+H)+ : 446.2403. Found: 446.2394.
EXAMPLE 1541 2-(R,S)-(3-methylphenylsulfonylamino)-3-[3-(4-amidinophenyl)-1-oxo-2,8-diazaspiro[4,5]dec-2-en-8-yl]propionic Acid Bis Trifluoroacetic Acid Salt
Part A: Methyl 2-(R,S)-(m-toluenesulfonylamino)-3-[3-(4-amidinophenyl)-1-oxo-2,8-diazaspiro[4,5]dec-2-en-8-yl]propionate hydrobromic acid salt.
m-Toluenesulfonyl chloride (63 mg, 0.33 mmol) was added to a mixture of the intermediate in Example SP1, Part D (0.200 g, 0.33 mmol) and triethylamine (0.14 mL, 1.0 mmol) in dimethylformamide (2 mL) and the mixture was stirred at room temperature for 19 h. Additional m-toluenesulfonyl chloride (14 mg, 0.07 mmol) was added and the mixture was stirred for 24 h. The solution was flash chromatographed using a graduated solvent system starting with chloroform and progressing to 30% methanol/chloroform to give 0.309 g of a tan solid. HRMS (FAB, glycerol) Calc. for (M+H)+ : 514.2124. Found: 514.2137.
Part B: 2- (R,S)-(m-Toluenesulfonylamino)-3-[3-(4-amidinophenyl)-1-oxo-2,8-diazaspiro[4,5]dec-2-en-8-yl]propionic acid bis trifluoroacetic acid salt.
The intermediate of Part A (0.277 g, 0.46 mmol) was suspended in 6M hydrochloric acid and the mixture was stirred at room temperature for 2 d. The mixture was concentrated and the residue was purified by Prep HPLC as described in Example 514A, Part B to give 16 mg of the title compound. HRMS (FAB, glycerol) Calc. for (M+H)+ : 500.1968. Found: 500.1956.
EXAMPLE 1552 (R,S)-(2-Piperidin-4-yl)ethyl-8-(3-carboxypropyl)-1-oxa-2,8-diazaspiro[4,4]non-2-ene-7,9-dione
This material was prepared using the procedures outlined in Example 189, giving the title compoind; mp: 133.4-135.1° C.; 1 H NMR (400 MHz, CD3 OD, 55° C.) δ 3.59 (t, J=6.8 Hz, 2H), 3.50 (d, J=17.7 Hz, 1H), 3.38 (bd, J=12.9 Hz, 2H), 3.18 (d, J=17.7 Hz, 1H), 2.98 (m, 4H), 2.85 (m, 2H), 2.50 (m, 1H, coincident with DMSO-d5), 2.45 (m, 2H), 2.31 (t, J=7.1 Hz, 2H), 2.00 (m, 2H), 1.98 (pentuplet, J=7.1 Hz., 2H), 1.40 (m, 2H).
EXAMPLE 1585A N2 -n-butyloxycarbonyl-N3 -[3- (4-piperidinylmethyl)-isoxazolin-5-(R,S)-yl-acetyl]-(S)-2,3-diaminopropionic Acid TFA Salt
1 HNMR (DMSO) δ 8.5 (1H, brd), 8.2 (1H, brd), 8.0 (1H, m), 7.4 (1H, d), 4.7 (1H, m), 3.9 (3H, m), 3.6 (1H, m), 3.25 (2H, m), 3.1 (3H, m), 2.9 (2H, m), 2.7 (1H, m), 2.4 (2H, m), 2.2 (3H; m), 1.8 (2H, m), 1.7 (1H, m), 1.5 (2H, m), 1.3 (4H, m), 0.9 (3H, t) ppm; ESI mass spectrum 427.1 (M+H)+ free base.
EXAMPLE 1603 Methyl N2 -n-butyloxycarbonyl-N3 -[3-(4-piperidinylpropyl)-isoxazolin-5(R,S)-yl-acetyl]-(S)-2,3-diaminopropionate TFA Salt
1 HNMR (CDCl3) δ 6.29 (1H, brd), 4.9 (1H, m), 4.45 (1H, m), 4.05 (2H, m), 3.78 (3H, s), 3.68 (1H, m), 3.5 (3H, m), 3.1 (1H, m), 2.96 (2H, m), 2.78 (1H, m), 2.55 (2H, m), 2.36 (2H, m), 1.95 (2H, m), 1.6 (6H, m), 1.5 (2H, m), 1.35 (5H, m), 0.94 (3H, m) ppm; ESI mass spectrum 455 (M+H)+ free base.
EXAMPLE 1609 Methyl N2 -p-toluenesulfonyl-N3 -[3-(4-piperidinylpropyl)-isoxazolin-5-(R,S)-yl-acetyl]-(S)-2,3-diaminopropionate TFA Salt
1 HNMR (CDCl3) δ 7.7 (2H, d), 7.3 (2H, d), 7.18 (1H, m), 6.4 (1H, m), 4.92 (1H, m), 4.0 (2H,m), 3.7 (1H, m), 3.58 (3H, d), 3.35 (2H, m), 3.1 (1H, m), 2.9 (2H, m), 2.75 (1H, m), 2.55 (1H, m), 2.4 (6H, m), 1.9 (2H, m), 1.6 (5H, m), 1.35 (2H, m) ppm; ESI mass spectrum 509.3 (M+H)+ free base
EXAMPLE 1619 N2 -(2-methylphenylsulfonyl)-N3 -[3-(4-piperidinylethyl)-isoxazolin-5-(R,S)-ylacetyl)-(S)-2,3-diaminopropionic Acid IFA Salt
1 HNMR (DMSO) δ: 8.5(1H, m), 8.18 (1H, m), 8.05 (1H, m), 7.79 (1H, d J=8.057 Hz), 7.51 (1H, t, J=6.958 & 7.324 Hz), 7.37 (2H, m), 4.65 (1H, m), 3.83(1H, m), 3.4 (1H, m), 3.27 (3H, m), 3.07 (1H, m), 2.84 (2H, m), 2.68 (1H, m), 2.59 (3H, s), 2.4 (1H, m), 2.32 (3H, m), 2.08 (1H, m), 1.83 (2H, m), 1.45 (3H, m), 1.26 (2H, m) ppm; ESI mass spectrum 481.4 (M+H, 100)+ free base.
EXAMPLE 1621 N2 -p-toluenesulfonyl-N3 -[3-(4-pieridinylethyl)-isoxazolin-5-(R,S)-ylacetyl]-(S)-2,3-diaminopropionic Acid TFA Salt
1 HNMR (DMSO) δ 7.73 (2H, d), 7.35 (2H, d), 4.85 (2H, m), 4.05 (1H, m), 3.63 (1H, m), 3.2 (2H, m), 3.0 (4H, m), 2.6 (1H, m), 2.4 (3H, s), 2.42 (2H, m), 2.0 (2H, m), 1.7 (1H, d), 1.6 (3H, m), 1.4 (3H, m) ppm; ESI mass spectrum 481 (M+H, 100)+ free base
EXAMPLE 1622 N2 -(2-bromophenylsulfonyl)-N3 -[3-(4-piperidinylethyl)-isoxazolin-5-(R,S)-ylacetyl]-(S)-2,3-diaminopropionic Acid TFA Salt
1 HNMR (DMSO) δ: 8.5 (1H, brd), 8.2 (1H, m), 8.1 (1H, m), 7.95 (1H, m), 7.8 (1H, m), 7.5 (2H, m), 4.7 (1H, m), 3.9 (1H, m), 3.4 (1H, m), 3.25 (2H, m), 3.2 (1H, m), 3.0 (1H, m), 2.8 (2H, m), 2.7 (1H, m), 2.4 (2H, m), 2.3 (2H, m), 2.2 (1H, m), 1.8 (2H, m), 1.5 (2H, m), 1.2 (2H, m) ppm; ESI mass spectrum 545.2 (M+H, 100)+ free base.
EXAMPLE 1623 N2 -(3,5-dimethylisoxazoylsulfonyl)-N3 -[3-(4-piperidinylethyl)-isoxazolin-5-(R,S)-ylacetyl]-(S)-2,3-diaminopropionic Acid TFA Salt
1 HNMR (DMSO) δ: 8.5 (1H, d), 8.08 (1H, m), 4.65 (1H, m), 3.9 (1H, m), 3.4 (1H, m), 3.25 (3H, m), 3.15 (2H, m), 2.85 (2H, m), 2.7 (1H, m), 2.52 (3H, s), 2.4 (1H, m), 2.3 (3H, m), 2.2 (3H, m), 1.8 (2H, brd, d), 1.45 (3H, m), 1.25 (2H, m) ppm; ESI mass spectrum 486.3 (M+H, 100)+ free base.
EXAMPLE 1624 N2 -(3,4-dimethylthiazoylsulfonyl)-N3 -[3-(4-piperidinylethyl)-isoxazolin-5-(R,S)-ylacetyl]-(S)-2,3-diaminopropionic Acid TFA Salt
1 HNMR (DMSO) δ: 8.6 (1H, d), 8.45 (1H, brd), 8.1 (1H, m), 4.65 (1H, m), 3.9 (1H, m), 3.5 (4H, m), 3.05 (2H, m), 2.9 (3H, m), 2.6 (3H, s), 2.45 (3H, s), 2.4 (5H, m), 1.8 (2H, brd. d), 1.5 (2H, m), 1.2 (2H, m) ppm; ESI mass spectrum 502.4 (M+H, 100)+ free base.
EXAMPLE 1625 N2 -n-butylsulfonyl-N3 -[3-(4-piperidinylethyl)-isoxazolin-5-(R,S)-ylacetyl]-(S)-2,3-diaminopropionic Acid TFA Salt
1 HNMR (DMSO) δ 8.5 (1H, m), 8.2 (2H, m), 7.55 (1H, m), 4.7 (1H, m), 3.9 (1H, m), 3.4 (1H, m), 3.2 (3H, brd, d), 3.1 (1H, m), 2.98 (2H, m), 2.9 (4H, m), 2.4 (1H, d), 2.3 (3H, m), 1.8 (2H, brd, d), 1.7 (2H, m), 1.5 (6H, m), 0.9 (3H, t) ppm; ESI mass spectrum 447.3 (M+H, 100)+ free base
EXAMPLE 1627 N2 -n-butyloxycarbonyl-N3 -[3-(4-piperidinylpropyl)-isoxazolin-5-(R,S)-yl-acetyl]-(S)-2,3-diaminopropionic Acid TFA Salt
1 HNMR (DMSO) δ 8.5 (1H, m), 8.2 (2H, brd),7.3 (1H, m), 4.7 (1H, m), 4.05 (1H, m), 3.9 (2H, t), 3.5 (1H, m), 3.2 (3H, brd, d), 3.0 (1H, m), 2.8 (2H, m), 2.7 (1H, m), 2.4 (1H, d), 2.25 (3H, m), 1.8 (2H, d), 1.6 (6H, m), 1.4 (7H, m), 0.9 (3H, t) ppm; ESI mass spectrum 441.3 (M+H, 100)+ free base.
EXAMPLE 1631 N2 -p-toluenesulfonyl-N3 -[3-(4-piperidinylpropyl)-isoxazolin-5-(R,S)-ylacetyl]-(S)-2,3-diaminopropionic Acid TFA Salt
1 HNMR (CD3 OD) δ: 7.7 (2H, m), 7.35 (2H, m), 4.85 (1H, m), 4.05 (2H, m), 3.72 (1H, m), 3.66 (2H, m), 3.56 (1H, m), 3.35 (2H, m), 3.25 (1H, m), 3.14 (1H, m), 2.94 (2H, m), 2.84 (1H, m), 2.55 (1H, m), 2.4 (3H, m), 2.35 (3H, m), 1.95 (2H, m), 1.62 (3H, m), 1.32 (4H, m), ppm; ESI mass spectrum 495.3 (M+H)+ free base
EXAMPLE 1656 N2 -m-toluenesulfonyl-N3 -[3-(4-amidinopiperidinyl)-isoxazolin-5-(R,S)-ylacetyl]-(S)-2,3-diaminoproprionic Acid
M.P. 70-74° C.; 1 H NMR (DMSO-d6) δ 8.13 (m,2H), 7.58 (m,2H), 7.44-7.38 (m, 5H), 4.74 (m, 1H), 3.88-3.80 (m, 5H), 3.40 (m, 1H), 3.14-2.99 (m, 4H), 2.74 (m,2H), 2.37 (s,3H), 2.17 (dd, J=7.32, 14.28 Hz), 1.88 (d, J=13.18 Hz, 2H), 1.53 (q, J=11.35 Hz, 2H) ppm; High Res Mass Spectrum calculated (M+H)+ 495.202580; found (M+H)+ 495.200904.
EXAMPLE 1657 N2 -p-toluenesulfonyl-N3 -[3-(4-amidinopiperidinyl)-isoxazolin-5-(R,S)-ylacetyl]-(S)-2,3-diaminoproprionic
Part A: The isoxazoline acetic acid was prepared starting from 1-t-butylcarbamate-4-piperidine carboxaldehyde (Jacobs, R., et al, EP 532177) through methods previously described. 1 H NMR (CDCl3) δ 4.94 (m, 1H), 4.18-4.05 (m, 2H), 3.18 (dd, J=10.25, 17.20 Hz, 1H), 2.90-2.67 (m, 4H), 2.63 (m, 2H), 1.87 (m, 2H), 1.56-1.45 (s, 9H), 1.46 (s, 9H) ppm; Mass Spectrum (NH3 -CI) m/z (M+NH4)+ 330 (100%); IR (KBr) 3100, 1734, 1690, 1648, 1430, 1276, 1168, 758 cm-1.
Part B: The acid from Part A (360 mg, 1.2 mmol) was coupled with methyl L-N2 -p-toluylsulfonyl-diaminoproprionate using procedure described in Example 43D. The crude product was chromatographed on silica gel (2% MeOH/CH2 Cl2) to afford 270 mg (41%) of a white foam. M.P. 55-60° C.; 1 H NMR (CDCl3) δ 7.72 (d, J=8.06 Hz, 2H), 7.30 (d, J=8.06 Hz, 2H), 6.45 (m, 1H), 5.73 (dd, J=8.42, 16.11 Hz, 1H), 4.90 (m, 1H), 4.13 (m, 2H), 4.01 (m, 1H), 3.58 (s, 3H), 3.60-3.49 (m, 2h), 3.10 (m, 1H), 2.84-2.72 (m, 3H), 2.57 (m, 2H), 2.48 (m, 1H), 2.42 (s, 3H), 1.85 (d, 2H), 1.55-1.46 (brd m, 2H), 1.46 (s, 9H) ppm; Mass Spectrum (NH3 -CI) m/z (M+NH4)+ 584 (100%); IR (KBr) brd 3300, 1746, 1688, 1428, 1238, 1164 cm-1.
Part C: To the product from Part B (230 mg, 0.41 mmol) was added 10 ml of 30% TFA/CH2 Cl2 and the mixture was stirred for 3h. The solvents were removed in vacuo. To the residue was added 2 ml DMF, triethylamine (0.39 ml, 2.8 mmol), and bis-tertbutyloxycarbonyl-3,5-dimethylpyrazole-1-carboxamidine (165 mg, 0.49 mmol) (Kim, et al, Tet. Lett.,1993, 34, 7677) and the mixture was stirred for 24 h. The reaction was partitioned with EtOAc/water. The organic layer was washed successively with water, brine and dried (MgSO4). Chromatography on silica gel (2% MeOH/CH2 Cl2) afforded 203 mg (71%) of a white foam. M.P. 69-75° C.; 1 H NMR (CDCl3) δ 10.18 (brd m, 1H), 7.72 (d, J=8.05 Hz, 2H), 7.30 (d, J=8 Hz, 2H), 6.40 (m, 1H), 5.65 (m, 1H), 4.87 (m, 1H), 4.30 (brd, 1H), 4.05 (brd, 1H), 3.60-3.51 (s+m, 5H), 3.09 (m, 3H), 2.78 (m, 3H), 2.42 (s, 3H), 1.89 (m, 2H), 1.73 (m, 2H), 1.63 brd m, 2H), 1.49 (s, 18H) ppm; Mass Spectrum (ESI) m/z (M+H)+ 709.5 (100%); IR (KBr) 3300-2800, 2210, 1742, 1660, 1600, 1546, 1446, 1332, 1162, 1092 cm-1.
Part D: To the product from Part C (160 mg, 0.23 mmol) was added 6 ml of 1:1 MeOH/water and lithium hydroxide (28 mg, 0.67 mmol). The mixture was stirred for 18 h and the solvents were removed in vacuo. The residue was taken up in water and acidified with 1N HCl and extracted with EtOAc. The organic layer was dried (MgSO4), filtered and concentrated to afford 118 mg (76%) of the acid. To the acid was added 10 ml 30% TFA/CH2 Cl2 and the mixture was stirred 24h. The solvents were removed and the TFA salt was purified by HPLC to afford 20 mg product. M.P. 134-140° C.; 1 HNMR (DMSO-d6) δ 7.9 (q, 1H), 7.66 (d, j=8.06 Hz, 2H), 7.46 (s, 3H), 7.36 (d, j=8.06 Hz, 2H), 4.72 (m, 1H), 3.80 (d, j=13.18 Hz, 2H) 3.61 (m, 1H), 3.41-3.18 (m, 5H), 3.13-2.99 (m, 3H), 2.75 (m 2H), 2.36 (s,3H), 2.22 (m, 1H), 1.88 (d, j=12.8 Hz, 2H), 1.53 (m, 2H) ppm ; Mass spectrum (ESI) m/z 495.2 (100%), high res Mass Spectrum (M+H)+ calculated 495.20258, found 495.202476
EXAMPLE 1673 N2 -p-toluenesulfonyl-N3 -[3-(4-amidinopiperidinylmethyl)-isoxazolin-5-(R,S)-ylacetyl]-(S)-2,3-diaminopropionic Acid TFA Salt
1 HNMR (DMSO) δ: 8.1 (2H, m), 7.65 (2H, d), 7.35 (2H, d), 4.7 (1H, m), 3.8 (3H, m), 3.4 (2H, m), 3.1 (1H, m), 3.0 (3H, m), 2.7 (1H, m), 2.4 (1H, m), 2.35 (3H, s), 2.25 (1H, m), 2.2 (3H, m), 1.85 (1H, m), 1.7 (2H, m), 1.6 (1H, m), 1.2 (3H, m) ppm; ESI mass spectrum 509.4 (M+H, 100)+ free base.
EXAMPLE 1704 N2 -n-butyloxycarbonyl-N3 -[3-(quanidinopropyl)-isoxazolin-5-(R,S)-ylacetyl]-(S)-2,3-diaminopropionic Acid TFA Salt
Part A: The title compound was prepared following the [3+2] cycloaddition methodology employed for example 4 from the readily accessible Boc-aminopropylchlorooxime (obtained from a sequence of steps from commerical (Aldrich) aminopropanol (aldehyde obtained via Moffat et. al. J. C. S. Perk. Trans. 1. 1991, 5, 1041-1051)) and butylvinyl ester. LiOH saponification in methanol:water (9:1), then afforded the desired acetic acid compound in 90% yield. 1 HNMR (CDCl3) δ 4.90 (m, 1H), 4.70 (brd, s, 1H), 3.08 (m, 3H), 2.68 (m, 2H), 2.57 (dd, 1H), 2.34 (t,2H), 1.75 (m, 2H), 1.41 (s, 9H) ppm; ESI mass spectrum 287(M+H, 100).
Part B: The product from part A was then coupled to methyl N2 -n-butyloxycarbonyl-(S)-2,3-diaminopropionate via the procedure used in example 4, to obtain Methyl N2 -n-butyloxycarbonyl-N3 -[3-(Boc-aminopropyl)isoxazolin-5-(R,S)-ylacetyl]-(S)-2,3-diaminopropionate in 50% yeild. Treatment with trifluoroaceticacid in dichloromethane, evaporation of solvent then afforded the anilino intermediate as the TFA salt. Standard guanidine formation techniques then afforded the di-Bocguanidinopropyl analog in 90% yield. Removal of the Boc-protecting groups with TFA afforded example 601 as the TFA salt. Alternatively, saponification of the methyl ester followed by removal of the Boc-protecting groups with TFA also afforded the desired product as the TFA salt in 80% overall yield. 1 H NMR (CD3 OD) δ: 4.93 (m, 1H), 4.29 (brd.m, 1H), 4.02 (t, 2H), 3.65 (m, 1H), 3.32 (m, 1H), 3.21 (m, 2H), 3.09 (dd, J=10.2 & 17.6 Hz, 1H), 2.79 (dd, J=7.32 & 17.1 Hz, 1H), 2.52 (dd, J=2.2 & 8.8 Hz, 1H), 1.84 (m, 2H), 2.39 (m, 3H), 1.58 (m, 2H), 1.36 (m, 2H), 0.9 (t, 3H,) ppm; HR MS calcd. for ESI mass spectrum 529 (M+H, 100) for free base.
EXAMPLE 1756 N2 -p-toluylsulfonyl-N3 -[3-(4-piperidinylmethylaminocarbonyl)-isoxazolin-5-(R,S)-ylacetyl]-(S)-2,3-diaminoproprionic Acid
Part A: To a mixture of tert-butyl vinylacetic acid (11.2 g, 0.079 mol) and ethylchlorooximidoacetate (11.37 g, 0.075 mol, Aldrich) in a mixture of 2:1 THF/water at 0° C. was added sodium bicarbonate (19.9 g, 0.237 mol). The reaction was stirred for 3d at room temperature, the layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine and dried with MgSO4. The crude oil was chromatographed on silica gel (7:1 hexanes/ EtOAc) to afford 7.46 g (39%) of product as a colorless oil; 1 H NMR (CDCl3) δ 5.15 (m, 1H), 4.39 (q, J=7.32 Hz, 2H),3.43 (dd, J=10.99, 17.58 Hz, 1H), 3.03 (dd, J=7.69, 17.58 Hz, 1H), 2.81 (dd, J=5.86, 16.11 Hz, 1H), 2.59 (dd, J=7.69, 16.11 Hz, 1H),1.46 (s, 9H), 1.39 (t, J=7.32 Hz, 3H); Mass Spectrum (NH3 -CI) m/z (M+H)+ 258 (12%), (M+NH4)+ 275 (100%).
Part B: The ethyl ester (3 g, 0.012 mol) from Part 1A was selectively hydrolyzed with LiOH (0.64 g, 0.015 mol) in 1.5:1 methanol/water at 0° C. for 1.5 h. The methanol was removed in vacuo. The aqueous residue was acidified with 10% citric acid and extracted with EtOAc and dried with MgSO4. The crude solid was recrystallized with CH2 Cl2 /hexanes to afford 2 g (75%) white crystals. mp 83-86° C.; 1 H NMR (CDCl3) δ 5.23 (m, 1H), 3.44 (dd, J=10.98, 17.58 Hz, 1H), 3.05 (dd, J=8.05, 17.95 Hz, 1H), 2.82 (dd, J=5.85, 16.11 Hz, 1H), 2.64 (dd, J=7.32, 16.11 Hz, 1H), 1.46 (s, 9H) ppm; Mass spectrum (NH3 -CI) m/z (M+NH4)+ 247 (90%).
Part C: 4-Aminomethyl piperidine (3.8 g, 0.034 mol, Aldrich) was selectively protected in 68% yield with carbobenzoxyimidazole using the method of Sharma, et al. (J. Med. Chem. 1989, 32, 357). To the crude 4-Cbz-aminomethyl piperidine (3 g, 0.012 mol) in 30 ml dioxane at 0° C. was added 13 ml of 1N sodium hydroxide and di-t-butyl dicarbonate (2.7 g, 0.013 mol). The reaction was stirred at room temperature for 48 h. The dioxane was removed in vacuo and the residue was suspended in EtOAc and washed successively with 10% citric acid, sat'd NaHCO3, brine and dried (MgSO4). Recrystallization with CH2 Cl2 /hexane afforded 1 g of white crystals (24%) mp 91-96°C.; 1 H NMR (CDCl3) δ 7.32 (s, 5H), 5.10 (s, 2H), 4.60 (t, 1H), 4.20 (brd, 2H), 3.0 (brd, 2H), 2.75 (brd, 2H), 1.65 (d, 2H), 1.45 (s, 9H), 1.12 (brd, 2H) ppm; Mass spectrum (NH3 -CI) m/z (M+H)+349 (31%), (M+H-56)+293 (100%); IR (KBr) 1698, 1530 cm-1 ; Analysis for C19H28N2O4 calc'd C:65.49, H:8.10, N:8.04; found C:65.78, H:7.82, N:8.06.
Part D: To the compound from part C (94 mg, 2.7 mmol) was added 50 ml EtOH and 100 mg of 10% Pd/C and the mixture was hydrogenated at 40 PSI for 18 h. Filtration and removal of the solvent afforded 569 mg (98%) solid. mp 84-88° C.; 1 H NMR (CDCl3) δ 4.70 (brd, 1H), 3.10 (d, 2H), 3.0 (t, 2H), 2.95 (brd, 2H), 2.64 (t, 2H), 1.70 (d, 2H), 1.46 (s, 9H), 1.20 (m, 2H) ppm; Mass spectrum (NH3 -CI) m/z (M+H)+ 215 (100%); IR (KBr) 2972-2800, 1694 cm-1.
Part E: To the acid from Part B (360 mg, 1.6 mmol) in 5 ml EtOAc was added triethylamine (0.67 ml, 4.80 mmol) followed by TBTU (560 mg, 1.73 mmol). After 15 minutes the amine from Part D (370 mg, 1.7 mmol) was added and the reaction was stirred for 24 h. The reaction mixture was washed successively with 10% citric acid, water, sat'd NaHCO3, brine and dried (MgSO4). The residue was chromatogrphed on silica gel (3:2 Hexanes/EtOAc) to afford 0.41 g (61%) white foam. 1 H NMR (CDCl3) δ 5.04 (m, 1H), 4.63 (d, J=13.18 Hz, 2H), 4.53 (d, J=13.18 Hz, 1H), 3.52-3.38 (m, 1H), 3.15-2.99 (m, 4H), 2.77 (m, 2H), 2.59-2.49 (m, 5H),1.78 (t, J=10.0 Hz 3H), 1.46 (s, 9H), 1.44 (s, 9H), 1.25 (m, 2H); Mass Spectrum (NH3-CI) m/z (M+H)+426.3 (29%), (M+H-56)+370.2 (43%); IR (KBr) 2976, 2930, 1714, 1632, 1592, 1522, 1476, 1452, 1392, 1366, 1168 cm-1.
Part F: To the product of Part E (380 mg, 0.89 mmol) was added 10 ml of 30% TFA/CH2 Cl2 and stirred for 4 h. The solvents were removed and 10 ml dioxane was added. The mixture was cooled to 0° C. and 2 ml of 1N NaOH was added followed by di-t-butyldicarbonate (0.22 g, 0.98 mmol). The reaction was stirred for 48 h at room temperature. The reaction was concentrated and partitioned with EtOAc and water. The aqueous layer was acidified with 10% citric acid, extracted with EtOAc and dried (MgSO4). The crude residue was chromatographed on silica gel (10% MeOH/CH2 Cl2) to afford 0.23 g (69%) of a white foam. mp 159-165° C. 1 H NMR (DMSO-d6) δ 6.95 (t, J=5.86 Hz, 1H), 4.87 (m, 1H), 4.33 (d, J=13.18 Hz, 1H), 4.09 (d, J=13.90 Hz, 1H), 3.31 (m, 1H), 3.07 (t, J=12.82 Hz, 1H), 2.99 (dd, J=3.66, 8.05 Hz, 1H), 2.93 (dd, J=3.66, 7.70 Hz, 1H), 2.82 (t, J=5.86 Hz, 2H), 2.69 (t, 12.82 Hz, 1H), 2.39 (m, 1H), 2.27 (dd, J=7.69, 14.6 Hz, 1H), 1.67-1.60 (m, 3H), 1.37 (s, 9H), 1.04 (t, J=13.5 Hz, 1H) ppm; Mass Spectrum (NH3-CI) m/z (M+NH4)+ 387 (100%); IR (KBr) 3352, 1692, 1630, 1588, 1518, 1448, 1210, 1176, 1140 cm-1.
Part G: The product of Part F (217 mg, 0.59 imol) was coupled with methyl L-N2 -p-toluylsulfonyl-diaminoproprionate according to procedure in Example 43D. The crude material was chromatographed on silica gel (2% MeOH/CH2 Cl2) to afford 230 mg (63%) foam. 1 H NMR (CDCl3) δ 7.72 (d, 2H), 7.30 (d, 2H), 6.40-6.32 (m, 1H), 5.1 (m, 1H), 4.70 (brd, 2H), 4.50 (d, 1H), 3.99 (brd, 1H), 3.65 (s, 3H), 3.50 (m, 2H), 3.15-2.99 (m, 3H), 2.85-2.55 (m 2H), 2.45 (s, 3H), 1.85 (brd, 4H), 1.46 (s, 9H), 1.29 (m, 2H) ppm; Mass Spectrum (ESI) m/z (M+H)+ 624.5 (72%), (M+H-56)+ 568.3 (98%).
Part H: The product of Part G (200 mg, 0.32 nmol) was hydrolyzed with lithium hydroxide (20 mg, 0.48 mmol) in 1:1 MeOH/water for 48 h. The solvents were removed in vacuo and the residue dissolved in water, acidified with 10% citric acid, extracted with EtOAc and dried (MgSO4). The crude acid was treated with 15 ml of 30% TFA/CH2 Cl2 for 24 h. The crude TFA salt was purified via HPLC to give 21 mg (11%) foamy solid. 1 HNMR (DMSO-d6) δ8.15 (m,1H), 7.73 (m,1H), 7.63 (d,j=8.06 Hz, 2H), 7.35 (d,j=8.05 Hz, 2H), 4.90 (m,1H), 4.37 (d,j=13.5 Hz, 2H), 4.14 (d,j=2H, j=10.9 Hz), 3.83 (q,j=9 Hz,1H), 3.35 (m,2H), 3.12-2.90 (m,3H), 2.74 (m, 2H), 2.33 (s,3H), 2.50-2.20 (m, 3H), 1.90-1.70 (m,4H), 1.35 (m,2H) ppm; High Res Mass Spectrum (M+H)+ calculated 510.202246, found 510.203464.
EXAMPLE 1769 N2 -p-toluenesulfonyl-N3 -[3-(N-(4-piperidinylmethyl)-N-(methyl)aminocarbonyl)isoxazolin-5-(R,S)-ylacetyl]-(S)-2,3-diaminopronrionic Acid Trifluoroacetic Acid Salt
Part A: To 4-tertButyloxycarbonyl-piperidinyl-methyl amine described previously (1.93 g, 0.009 mol) in 20 ml CH2 Cl2 at 0° C. was added pyridine (1.1 ml, 0.014 mol) followed by slow addition of trifluoroacetic anhydride (1.4 ml, 0.009 mol). The reaction was stirred at 0° C. for 1 h, then it was diluted with CH2 Cl2 washed successively with 10% citric acid, water, sat'd NaHCO3, brine and dried (MgSO4). Recrystallization from CH2 Cl2 /Hexanes afforded 2.4 g (86%) of a bright yellow solid. mp 123-125° C.; 1 H NMR (CDCl3) δ 4.74 (m, 1H), 4.56 (d, J=13 Hz, 1H), 4.0 (d, J=12 Hz, 1H), 3.14 (m, 3H), 2.75 (t, J=13 Hz, 1H), 1.82 (d, 3H), 1.45 (s, 9H) 1.28 (m, 2H) ppm; Mass Spectrum (NH3 -CI) m/z (M+NH4)+ 328 (100%), (M+NH4 -56)+272.1 (100%); IR (KBr) 3354, 1686, 1526, 1200, 1140 cm-1.
Part B: To the product of Part A (400 mg, 1.29 mmol) in 2 ml DMF was added NaH (62 mg, 1.6 mmol) After 1 h, methyl iodide (0.1 ml, 1.6 mmol) was added and the reaction was immersed in a 60° C. oil bath for 24 h. The reaction was cooled and partioned between EtOAc and water. The organic layer was washed with water, brine and dried (MgSO4). The reaction had not gone to completion and was resubjected to the above conditions and after work up afforded 322 mg (77%) yellow oil. The crude trifluoroacetate was placed in 20 ml of 1:1 MeOH/water and K2 CO3 (150 mg, 1.1 mmol) was added and the reaction was stirred for 36 h. The solvents were removed in vacuo and the residue partioned with EtOAc/water. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with brine and dried (MgSO4), filtered and concentrated to yield 194 mg (89%) oil. 1 H NMR (CDCl3) δ 3.15 (m, 4H), 2.85 (s, 3H), 2.80 (brd s, 1H), 2.61 (t, J=12Hz, 2H), 1.63 (d, J=10.6 Hz, 2H), 1.45 (s, 9H), 1.25 (m, 2H), 0.87 (m, 1H) ppm; Mass Spectrum (NH3 -CI) m/z (M+H)+ 229 (100%), (M+NH4)+ 246 (15%); IR (KBr) 2924,1696,1160 cm-1.
Part C: The product of Part B (173 mg, 0.76 mmol) was coupled with the acid (from Part B previous example) according to procedure in Example 43D to yield 177 mg (54%) yellow oil. 1 H NMR (CDCl3) δ 5.02 (m, 1H), 4.59-4.50 (brd m, 2H), 3.48 (dd, J=10.62,17.58 Hz, 1H), 3.15-3.02 (m, 4H), 2.86 (s, 3H), 2.77 (m, 2H), 2.59 (m, 1H), 2.0-1.91 (brd m, 1H), 1.73 (t, J=11.72 Hz, 2H), 1.46 (s, 18H), 1.28 (m, 2H) ppm; Mass Spectrum (NH3 -CI) m/z (M+H)+ 440.2 (100%), (M+NH4)+ 457.3 (23%), (M+H-56)+ 384.2 (73%); IR (KBr) 2976, 2932, 1730, 1694, 1634, 1162 cm-1
Part D: The product of Part C (170 mg, 0.387 mmol) was deprotected and selectively reprotected as in Part 1F to afford a yellow foam. 1 H NMR (CDCl3) δ 5.10 (m, 1H), 4.60 (m, 1H), 4.50 (m, 1H), 3.50 (m, 1H), 3.12 (m, 4H), 2.80 (s, 3H), 2.78 (m, 1H), 2.70 (m, 2H), 1.90 (brd m, 1H), 1.75 (brd m, 2 H), 1.45 (s, 9H), 1.25 (brd m, 2H) ppm; Mass Spectrum (NH3 -CI) m/z (M+NH4)+ 401 (100%).
Part E: The product of Part D (148 mg, 0.386 mmol) was coupled with methyl L-N2 -p-toluylsulfonyl-diaminoproprionate according to the procedure in Example 43D. The crude material was chromatographed on silica gel (3% MeOH/CH2 Cl2) to afford 230 mg clear glass containing minor impurities. 1 H NMR (CDCl3) δ 7.72 (d,2H), 7.33 (d,2H), 6.35 (m, 1H), 5.10 (m,1H), 4.61 (brd m, 1H), 4.45 (brd m, 1H), 3.97 (brd m, 1H), 3.63-3.54 (s+m, 5H), 3.48-3.30 (m, 2H), 3.15 (brd m,4H), 2.85 (s, 3H), 2.75-2.5 (m, 4H), 2.45 (s, 3H), 1.78 (brd m, 2H), 1.46 (s,9H), 1.30 (m, 2H) ppm; Mass Spectrum (ESI) m/z (M+H)+ 638.5 (100%)
Part F: The product of Part E (230 mg, 0.36 mmol) was subjected to hydrolysis and deprotection and purification by HPLC to afford 134 mg (58%) of a white powder. mp 69-72° C.; 1 HNMR (DMSO-d6) δ 8.35 (brd m, 2H), 8.10 (brd m, 2H), 7.65 (d, J=6.96 Hz, 2H), 7.35 (d, j=8.05 Hz, 2H), 4.83 (m,1H), 4.36 (d,j=13.6 Hz, 1H), 4.12 (d,j=10 Hz, 1H), 4.0-3.5 (m,6H), 3.35 (m,1H), 3.14 (t,j=10.98 Hz, 1H),2.83 (m,1H), 2.59 (s, 3H), 2.55 (m,1H), 2.36 (s, 3H), 2.35 (m,1H), 2.0 (brd m,1H), 1.80-1.74 (brd m, 2H), 1.18 (m, 2H) ppm; Mass Specturm (ESI) m/z (m+H)+ 524.4 (100%); IR (KBr) 3300-2800 brd, 1736,1632, 1202,1162 cm-1.
EXAMPLE 1774 N2 -p-toluylsulfonyl-N3 -[3-(4-piperidinylaminocarbonyl)isoxazolin-5-(R,S)-ylacetyl]-(S)-2,3-diaminoproprionate
Part A: The acid (from Part B described previously, 225 mg, 0.98 mmol) was coupled with 1-tertbutyloxycarbonyl-4-aminopiperidine (Obase, H; et al, J.Het. Chem. 1983, 20, 565) as described in Example 43D.A white foam was obtained in 78% yield. 1 H NMR (CDCl3) δ 6.50 (d, J=8.05 Hz, 1H), 5.13 (m, 1H), 3.43 (dd, J=10.62, 17.95 Hz, 1H), 3.04 (dd, J=7.69, 18.3 Hz, 1H), 2.87 (t, J=12.45 Hz, 2H), 2.76 (dd, J=6.22, 16.11 Hz, 1H), 2.57 (dd, J=6.95, 16.11 Hz, 1H), 1.94 (d, J=9.88 Hz, 2H), 1.46 (s,18H), 1.41 (m, 2H) ppm; Mass Spectrum (NH3 -CI) m/z (M+H)+ 412.2 (69%), (M+NH4)+ 429.3 (50%), (M+NH4 -56)+ 373.2 (100%); IR (KBr) 3424,2866,1728,1692,1536,1426,1368,1238,1162 cm-1.
Part B: The product of Part A (300 mg, 0.73 mmol) was deprotected with TFA and selectively reprotected with di-t-butyldicarbonate to afford 270 mg of a white foam. 1 H NMR (CDCl3) δ 6.64 (d, J=8.05 Hz, 1H), 5.2 (m, 1H), 4.10-3.95 (m, 3H), 3.47 (dd, J=10.99, 17.96 Hz, 1H), 3.08 (dd, J=7.69, 17.95 Hz, 1H), 2.89 (t+dd, 3H), 2.72 (dd, J=6.95, 16.11 Hz, 1H), 1.94 (d, J=12.82 Hz, 2H), 1.46 (s, 9H), 1.46 (brd m, 2H) ppm; Mass Spectrum (NH3 -CI) m/z (M+NH4)+ 373 (100%).
Part C: The product of Part B (260 mg, 0.73 mmol) was coupled with methyl L-N2 -p-toluylsulfonyl-diaminoproprionate according to the procedure in Example 43D. The crude foam was chromatographed on silica gel (2% MeOH/CH2 Cl2) to afford 289 mg (65%) of a white foam. 1 H NMR (CDCl3) δ 7.71 (d, J=8.06 Hz, 2H), 7.31 (d, J=8.42 Hz, 2H), 6.65 (dd, J=6.59 Hz, 1H), 6.36 (t, J=5.86 Hz, 1H), 5.15 (m, 1H), 4.10-3.96 (m, 4H), 3.63-3.56 (s+m, 5H), 3.45-3.35 (m, 1H), 3.09 (m,1H), 2.85 (t, J=12.45 Hz, 2H), 2.62 (m, 2H), 2.43 (s, 3H), 1.94 (d, J=12.82 Hz, 2H), 1.45 (s+m, 9+2H) ppm; Mass Spectrum (ESI) m/z (M+H)+ 610.3 (100%).
Part D: The product of Part C (289 mg, 0.47 mmol) was subjected to hydrolysis and deprotection and purification as previously described to afford 224 mg (78%) white powder. mp 88-91° C.; 1 HNMR (DMSO-d6) δ 8.66-8.57 (d+m, j=7.69Hz, 2H), 8.30 (brd m, 1H), 8.07 (m, 2H), 7.64 (d,j=8.06 Hz, 2H), 7.35 (d,j=8.06 Hz, 2H), 4.94 (m,1H), 3.96 (m, 1H), 3.87 (q,j=6.95 Hz, 1H), 3.30-3.24 (m,4H), 3.08-2.89 (m,4H), 2.46 (m,1H), 2.37 (s,3H), 2.37 (m,1H), 1.87 (d,j=10.9 Hz,2H), 1.73 (q,j=10.6 Hz,2H) ppm; Mass Spectrum (ESI) m/z (M+H)+ 496.3 (100%); IR (KBr) 3300-2800 brd, 1736,1666, 1544 1162 cm-1
EXAMPLE 1945 N2 -3-Methylphenylsulfonyl-N3 -[3-[2-(piperidin-4-yl)ethyl]isoxazolin-5(R,S)-ylacetyl)-(S)-2,3-diaminopropionic Acid TFA Salt
Part A: Methyl (3-(2-N-t-Butyloxycarbonylpiperidin-4-yl)ethyl)isoxazolin-5(R,S)-ylacetate
To a solution of Methyl Vinylacetate 352 g, 0.35 mol) in CH2 Cl2 (175 mL) was added a 5% solution of sodium hypochlorite (210 mL, 0.15 mol). The mixture was stirred rapidly at room temperature and a solution of (3-N-t-butyloxycarbonylpiperidin-4-yl)propanal oxime (Example 189, Part B, 17.60 g, 68.6 mmol) in CH2 Cl2 (50 mL) was added over 15 h. The mixture was diluted with water and CH2 Cl2, the layers separated, and the aqueous washed with CH2 Cl2. The combined organic was dried (MgSO4), concentrated in vacuo, and the oily residue purified using flash chromatography (10-50% EtOAc/hexanes step gradient), giving 10.35 g (42%) of the desired isoxazoline as a golden oil; Anal. Calcd for C18 H30 N2 O5 : C, 61.00; H, 8.53; N, 7.90. Found: C, 61.07; H, 8.50; N, 7.80.
Part B: (3-(2-N-t-Butyloxycarbonylpiperidin-4-yl)ethyl)isoxazolin-5(R,S)-ylacetic Acid
To a solution of methyl (3-(2-N-t-butyloxycarbonylpiperidin-4-yl)ethyl)isoxazolin-5(R,S)ylacetate (10.35 g, 29.20 mmol) in THF (100 mL) was added 0.5 M LiOH (80 mL, 40 mmol). The resulting solution was stirred at room temperature overnight (18 h) and then concentrated in vacuo to one-half volume. The pH was adjusted to 4, and the resulting cloudy solution washed with CH2 Cl2 (4×30 mL). The combined organic was dried (MgSO4), concentrated in vacuo, and placed under vacuum until constant weight was achieved, affording 9.74 g (98%) of the desired acid; Anal. Calcd for C17 H28 N2 O5 : C, 59.98; H, 8.29; N, 8.23. Found: C, 60.19; H, 8.42; N, 7.87.
Part C: t-Butyl N2 -3-Methylphenylsulfonyl-N3 -[(3-(N-t-butyloxycarbonyl-2-piperidin-4-yl)ethyl)isoxazolin-5(R,S)-ylacetyl]-(S)-2,3-diaminopropionate
To a solution of (3-(2-N-t-butyloxycarbonylpiperidin-4-yl)ethyl)isoxazolin-5(R,S)-ylacetic acid (165 mg, 0.485 mmol) and t-butyl N2 -3-methylphenylsulfonyl-(S)-2,3-diaminopropionate hydrochloride (170 mg, 0.485 mmol) in DMF (5 mL) was added Et3 N (0.2 mL, 1.4 mmol) followed by TBTU (160 mg, 0.498 mmol). The resulting mixture was stirred for 4 h at room temperature, then was diluted with EtOAc (50 mL). It was washed with water (4×20 mL), sat. NaHCO3 (30 mL), sat. NaCl and dried (MgSO4). Concentration in vacuo followed by placing the material under vacuum until constant weight was achieved afforded 271 mg (88%) of the desired amide; MS (ESI, e/z, relative intensity): 637 (M+H)+, 20%, 537 (M+H-C4 H9 CO2)+, 51%.
Part D: N2 -3-Methylphenylsulfonyl-N3 -[(3-(2-piperidin-4-yl)ethyl)isoxazolin-5(R,S)-ylacetyl]-(S)-2,3-diaminopropionic Acid TFA Salt
To a solution of t-butyl N2 -3-methylphenylsulfonyl-N3 -[(3-(N-t-butyloxycarbonyl-2-piperidin-4-yl)ethyl)isoxazolin-5(R,S)-ylacetyl]-(S)-2,3-diaminopropionate (261 mg, 0.410 mmol) in CH2 Cl2 (2 mL) was added TFA (2 mL, 26 mmol). After 2 h at room temperature, the solution was concentrated in vacuo and the residue triturated with ether (3×5 mL). The resulting white powder was purified using reverse phase HPLC, giving 202 mg (83%) of the desired piperidine; MS (ESI, e/z, relative intensity): 481 (M+H)+, 100%.
EXAMPLE 2103 N2 -(3,5-dimethylisoxazole-4-sulfonyl)-N3 -[3-(4-amidinophenyl)isoxazolin-5(R,S)-ylacetyl]-(S)-2,3-diaminopropionate Trifluoroacetate Salt
Part A: Methyl N2 -(3,5-Dimethylisoxazole-4-sulfonyl)-N3 [3-(4-N-t-butoxycarbonylamidinophenyl)isoxazolin-5(R S)-ylacetyl]-(S)-2,3-diaminopropionate
Methyl N2 -(3,5-dimethylisoxazole-4-sulfonyl)-N3 -Boc-(S)-2,3-diaminopropionate (1.40 mmole) was stirred with 4 M HCl/dioxane (10 mL, 40 mmol) at 25° C. After 2.5 h, the volatiles were removed in vacuo, and residual HCl/dioxane was removed by repeated addition of toluene and evaporation. To the residue was added 3-(4-N-t-butoxycarbonylamidinophenyl)isoxazolin-5(R,S)-ylacetic acid (510 mg, 1.47 nmol), TBTU (480 mg, 1.50 mmole) and DMF (15 mL). Triethylamine (0.830 mL, 603 mg, 5.97 mmole) was added and the reaction mixture was stirred at 25° C. overnight. The mixture was diluted with water (70 mL) extracted with 3× ethyl acetate. The combined organic extracts were washed with 2× water, 5% pH 4 potassium hydrogen phthalate buffer (25 mL), 5% aqueous sodium bicarbonate (25 mL) and brine. After drying over MgSO4, removal of volatiles and purification by flash chromatography (ethyl acetate) provided 0.598 g of the desired product in 96% purity, as assessed by analytical HPLC (4.6 mm×25 cm C18 reverse phase, 1 mL/min, 0.05% TFA/10-90% AcCN/water gradient over 20 min, product at 12.9 min); 1 H NMR (300 MHz, CDCl3) δ 7.84 (m, 2H), 7.63 (m, 2H), 6.52 (bm, 1H), 6.07 (bd, 1H), 5.11 (bm, 1H), 4.02 (bm, 1H), 3.66/3.67 (2s, 3H, diastereomers, methyl ester), 3.67-3.45 (m, 3H), 3.15 (m, 1H), 2.60/2.61 (2s, 3H, diastereomers, isoxazole methyl), 2.76-2.55 (m, 2H), 2.38/2.41 (2s, 3H, diastereomers, isoxazole methyl), 1.56 (s, 9H, t-Bu); MS (ESI): m/e 607.2 (M+H)+.
Part B: N2 -(3,5-Dimethylisoxazole-4-sulfonyl)-N3 -[3-(4-N-t-butoxycarbonylamidinophenyl)isoxazolin-5(R,S)-ylacetyl]-(S)-2.3-diaminopropionate
To a solution of 200 mg (0.329 mmole) of methyl N2 -(3,5-dimethylisoxazole-4-sulfonyl)-N3 [3-(4-N-t-butoxycarbonyl-amidinophenyl)isoxazolin-5(R,S)-ylacetyl]-(S)-2,3-diamino-propionate in 15 mL of THF/MeOH/water 1:1:1 was added 138 mg (3.29 mmole) of LiOH. After 2 h, analytical HPLC (see conditions in Part A, product at 11.7 min) indicated the reaction was 97% complete. Removal of volatiles and purification by flash chromatography provided 0.164 g 91% pure (see HPLC conditions in Part A) of the desired product as a mixture of free acid and lithium salt (as indicated by 0.55% Li by elemental analysis); 1 H NMR (300 MHz, DMSO-d6) δ 8.02 (d, J=8.0 Hz, 2H), 7.96 (m, 1H), 7.75 (dd, J=1.5, 8.4 Hz, 2H), 5.02 (m, 1H), 3.58-3.08 (m, 5H), 2.55 (s, 3H, isoxazole methyl), 2.60-2.37 (m, 2H), 2.34 (s, 3H, isoxazole methyl), 1.45 (s, 9H, t-Bu); MS (ESI): m/e 593.3 (M+H)+, m/e 493.2 (M-Boc)+.
Part C: N2 -(3,5-dimethylisoxazole-4-sulfonyl)-N3 -[3-(4-amidinophenyl)isoxazolin-5(R,S)-ylacetyl]-(S)-2,3-diaminopropionate Trifluoroacetate Salt
A solution of 137 mg (0.231 mmole) of N2 -(3,5-dimethylisoxazole-4-sulfonyl)-N3 [3-(4-N-t-butoxycarbonyl-amidinophenyl)isoxazolin-5(R,S)-ylacetyl]-(S)-2,3-diamino-propionate in 4 mL of CH2 Cl2 and 2 mL of TFA was stirred for 4 h, then diluted with 60 mL of ether. The precipitate was dried to give 0.103 g of the desired product as a white solid, which was determined to be 96% pure by analytical HPLC (see HPLC conditions in Part A); 1 H NMR (300 MHz, DMSO-d6) δ 9.79 (bs, 1H), 9.72 (bs, 1H), 9.29 (bs, 2H), 8.25 (bs, 1H), 8.16 (m, 1H), 7.87 (s, 4H), 5.02 (bm, 1H), 3.78 (bs, 1H), 3.60-3.08 (m, 4H), 2.54 (s, 3H, isoxazole methyl), 2.34 (s, 3H, isoxazole methyl), 2.62-2.34 (m, 2H); MS (ESI): m/e 493.3 (M+H)+ ; HRMS (FAB): m/e calculated for C20 H25 N6 O7 S (M+H)+ 493.150544; found 493.148681.
EXAMPLE 2103a N2 -(3,5-dimethylisoxazole-4-sulfonyl)-N3 -[3-(4-amidinophenyl)isoxazolin-5(R)-ylacetyl]-(S)-2,3-diaminopropionate Trifluoroacetate Salt (Alternative Hydrolysis Procedure)
Methyl N2 -(3,5-dimethylisoxazole-4-sulfonyl)-N3 -[3-(4-amidinophenyl)isoxazolin-5(R)-ylacetyl]-(S)-2,3-diaminopropionate hydrochloride salt (Part B, replacing ammonium acetate with ammonium chloride, 1.3 g, 2.6 mmol) was stirred in 6N HCl (150 ml) at room temperature for 20 hours. Solvent was evaporated under reduced pressure to give the crude hydrochloride salt as a white solid (1.1 g, 87%). Purification of 0.17 g crude product by preparative HPLC (Vydac C18 reverse phase column; 2×25 cm; 10 ml/min flow rate; 254 nM; gradient: from 100% H2 O with 0.05% TFA to 20% H2 O and 80% CH3 CN with 0.05% TFA in 50 minutes) yielded 0.12 g (70.6%) of the title compound as a white powder. Chiral HPLC analysis (SFC, Chiralcel OD; 0.46×25 cm; 30° C.; 2.0 ml/min flow rate; 0.1% TFA/22% MeOH/78% CO2 ; 280 nM; 150 atm) showed >99% d.e. with respect to the (S,S)-diastereomer and >98% chemical purity. MS (ESI): m/e 493 (M+H)+. HRMS (FAB): m/e calculated for C20 H24 N6 O7 S (M+H)+ 493.150649; Found 493.150544.
EXAMPLE 2103b N2 -(3,5-Dimethylisoxazole-4-sulfonyl)-N3 -[3-(4-amidinophenyl)isoxazolin-5(R)-ylacetyl]-(S)-2,3-diaminopropionic Acid Methanesulfonate Salt
Part A: Methyl N2 -(3,5-Dimethylisoxazole-4-sulfonyl)-N3 [3-(4-(cyanophenyl)isoxazolin-5(R)-ylacetyl]-(S)-2,3-diaminopropionate
To a suspension of 3-(4-cyanophenyl)isoxazolin-5(R)-ylacetic acid (252 mg, 0.725 mmol), methyl N2 -(3,5-dimethylisoxazole-4-sulfonyl-(S)-2,3-diaminopropionate hydrochloride (28.24 g, 70% purity, 63.0 mmol) in DMF (200 mL) was added TBTU (28.90 g, 90 mmol). The mixture was cooled to 0° C. and Et3 N (31.4 mL, 225 mmol) was added dropwise. The resulting mixture was allowed to warm to room temperature overnight (18 h), then was diluted with EtOAc (500 mL). It was washed with water (4×200 mL), sat. NaHCO3 (100 mL), sat. NaCl (100 mL) and dried (MgSO4). Concentration in vacuo followed by placing the material under vacuum until constant weight was achieved afforded 25.06 g (81%) of the desired amide; 1 H NMR (300 MHz, CDCl3) δ 8.77 (bs, 1H), 8.22 (t, J=5.9 Hz, 1H), 5.02 (m, 1H), 3.98 (t, J 7.0 Hz, 1H), 3.55 (dd, J=17.2, 10.6 Hz, 1H), 3.48 (s, 3H), 3.42 (m, 1H), 3.16 (m, 2H), 2.54 (s, 3H, coincident with m, 1H, DMSO-d5), 2.37 (dd, J=14.6, 7.0 Hz, 1H), 2.33 (s, 3H).
Part B: Methyl N2 -(3,5-Dimethylisoxazole-4-sulfonyl)-N3 -[3-(4-amidinophenyl)isoxazolin-5(R)-ylacetyl]-(S)-2,3-diaminopropionate Acetate Salt
Into a solution of methyl N2 -(3,5-dimethylisoxazole-4-sulfonyl)-N3 [3-(4-(cyanophenyl)isoxazolin-5(R)-ylacetyl]-(S)-2,3-diaminopropionate (25.06 g, 51.17 mmol) in anhydrous MeOH (750 mL) at 0° C. was bubbled HCl gas for 3 hours. The resulting solution was then allowed to warm to room temperature overnight (18 h), after which the solvent was evaporated in vacuo, to give an oil. The oily residue was triturated with ether (3×100 mL) and the resulting solid placed under vacuum until constant weight was achieved. The crude imidate was then dissolved in MeOH (1 L) and ammonium acetate (20.0 g, 259 mmol) added. The resulting mixture was stirred at room temperature for 18 h, then concentrated in vacuo. The residue was then crystallized from EtOH, giving 21.75 g of crude amidine. A portion of this material (8.5 g) was purified using flash chromatography (20% MeOH-EtOAc) to give 3.77 g (33%) of 97.6% pure amidine (analytical HPLC: 4.6 mm×25 cm C18 reverse phase, 1 mL/min, 0.05% TFA/10-90% AcCN/water gradient over 20 min); 1 H NMR (300 MHz, DMSO-d6) δ 8.26 (bt, 1H), 7.86 (m, 4H), 5.01 (m, 1H), 3.96 (t, J=6.6 Hz, 1H), 3.56 (dd, J=17.2, 10.6 Hz, 1H), 3.48 (s, 3H, coincident with m, 1H), 3.18 (m, 2H), 2.53 (s, 3H, coincident with m, 1H, DMSO-d5), 2.54 (s, 3H), 2.36 (dd, J=14.6, 7.0 Hz, 1H), 2.32 (s, 3H), 1.74 (s, 3H); MS (ESI): m/e 507.3 (M+H)+.
Part C: N2 -(3,5-Dimethylisoxazole-4-sulfonyl)-N3 [3-(4-amidinophenyl)isoxazolin-5(R)-ylacetyl]-(S)-2,3-diaminopropionic Acid (Enzymatic Hydrolysis)
To a solution of methyl N2 -(3,5-dimethylisoxazole-4-sulfonyl-N3 [3-(4-amidinophenyl)isoxazolin-5(R)-ylacetyl]-(S)-2,3-diaminopropionate HOAc salt (1.866 g, 3.29 mmol) in 0.4 N Hepes buffer (pH 7.1, 220 mL, 15 mmol) was added rabbit liver esterase (3.6 M crystalline suspension in ammonium sulfate, 2000 units, Sigma). The resulting solution was incubated at 37° C. for 60 hours. Protein was removed from the reaction mixture by ultra filtration (Amicon YM-10 membrane), and the filtrate was then concentrated in vacuo and lyophilized. Purification using a reverse phase silica column (5×9.5 cm in water; crude product loaded as an aqueous solution followed by elution with water (1200 mL) and by 500 mL each of 5, 10, 20 and 30% CH3 CN-H2 O. Fractions containing the desired product were pooled, acetonitrile was removed and the aqueous solution lyophilized to yield 1.5 g (93%) of pure zwitterion; 1 H NMR (300 MHz, DMSO-d6) δ 7.93 (t, 1H), 7.76 (s, 4H), 4.98 (m, 1H), 3.17-3.50 (m, 5H, coincident with water), 2.66 (dd, 1H), 2.56 (s, 3H), 2.35 (s, 3H), 2.36 (dd, 1H); MS (ESI): m/e 493.3 (M+H)+.
Part D: N2 -(3,5-Dimethylisoxazole-4-sulfonyl)-N3 [3-(4-amidinophenyl)isoxazolin-5(R)-ylacetyl]-(S)-2,3-diaminopropionic Acid Methanesulfonic Acid Salt
To a solution of the zwitterion (2.75 g, 5.43 mmol) in 50% CH3 CN--H2 O (135 mL) was added methanesulfonic acid (0.57 g, 5.97 mmol). The reaction mixture was stirred at room temperature for 1 h, resulting in a clear solution. Solvents were removed in vacuo and the residue placed under vacuum for several hours. The crude mesylate was dissolved in hot acetone and water until the solution was clear (120 mL total volume). After hot filtration the solution was allowed to cool slowly and was then refrigerated for 24 h. The resulting white precipitate was filtered and dried under vacuum, affording 1.72 g (52%) of the title compound; 1 H NMR (300 MHz, DMSO-d6) δ 9.37 (bs, 2H), 9.03 (bs, 2H), 8.57 (d, J=9.5 Hz, 1H), 8.23 (t, J=5.9 Hz, 1H), 7.88 (s, 4H), 5.03 (m, 1H), 3.91 (m, 2H), 3.57 (dd, J=17.2, 10.6 Hz, 1H), 3.44 (m, 1H), 3.21 (dd, J=17.6, 7.7 Hz, 1H), 3.09 (m, 1H), 2.58 (dd, J=14.6, 6.6 Hz, 1H), 2.54 (s, 3H), 2.38 (dd, J=14.6, 7.3 Hz, 1H), 2.33 (s, 3H, MsOH); MS (ESI): m/e 493.2 (M+H)+ ; Anal. Calcd. for C21 H28 N6 O10 S2 : C, 42.85; H, 4.79; N, 14.05; S, 10.89. Found: C, 42.45; H, 4.74; N, 14.05; S, 11.19.
EXAMPLE 2420 Methyl N2 -n-butyloxycarbonyl-N3 -[3-(4-piperidinylpropyl)isoxazolin-5-(R,S)-ylformyl)-(S)-2,3-diaminopropionate TFA salt
1 HNMR (CDCl3) δ 7.38 (1H, brd), 6.95 (1H, brd), 5.65 (1H, m), 4.98 (1H, m), 4.42 (1H, m),4.06 (2H, m), 3.76 (3H, s), 3.65 (2H, m), 3.48 (2H, m), 3.25 (2H, m), 2.95 (2H, m), 2.4 (2H, m), 1.95 (2H, brd), 1.6 (5H, m), 1.48 (2H, m), 1.35 (4H, m), 0.94 (3H, m) ppm; ESI mass spectrum 441 (M+H)+ free base
EXAMPLE 2421 Methyl N2 -p-toluenesulfonyl-N3 -[3-(4-piperidinylpropyl)-isoxazolin-5-(R,S)-ylformyl]-(S)-2,3-diaminopropionate TFA salt
1 HNMR (CDCl3) δ: 7.8 (1H, m), 7.68 (2H, m), 7.3 (3H, m), 5.7 (1H, m), 4.92 (1H, m), 4.1 (1H, m), 4.0 (1H, m), 3.7 (2H, m), 3.55 (3H, s), 3.45 (3H, m), 2.9 (2H, brd), 2.4 (3H, s), 2.38 (2H, m), 1.9 (3H, m), 1.65 (2H, m), 1.54 (2H, m), 1.35 (2H, m) ppm; ESI mass spectrum 495.3 (M+H)+ free base.
EXAMPLE 2422 N2 -p-toluenesulfonyl-N3 -[3-(4-piperidinylpropyl)isoxazolin-5-(R,S)-ylformyl]-(S)-2,3-diaminopropionic acid TFA salt
1 HNMR (CD3 OD) δ: 7.7 (2H, m), 7.32 (2H, m), 4.85 (1H m), 4.1 (1H, m), 3.75 (1H, m), 3.65 (2H, m), 3.32 (3H, m), 3.2 (2H, m), 2.9 (2H, m), 2.4 (5H, m), 1.95 (2H, m), 1.62 (3H, m), 1.35 (4H, m),ppm; ESI mass spectrum 481.3 (M+H)+ free base
EXAMPLE 2423 N2 -n-butyloxycarbonyl-N3 -[3-(4-piperidinylpropyl)isoxazolin-5-(R,S)-ylformyl]-(S)-2,3-diaminopropionic acid TFA salt
1 HNMR (CD3 OD) δ: 4.92 (1H, m), 4.3 (1H.sub., m), 4.05 (2H, m), 3.6 (2H, m), 3.38 (3H, m), 3.15 (1H, m), 2.95 (2H, m), 2.35 (2H, m), 1.95 (2H, m), 1.6 (5H, m), 1.35 (6H, m), 0.95 (3H, m) ppm; ESI mass spectrum 427.3 (M+H)+ free base.
EXAMPLE 2500 Methyl N3 -Boc-(S)-2,3-diaminopropionate
Part A: Methyl N2 -Cbz-L-2,3-diaminopropionate HCl Salt
To a solution of N2 -Cbz-L-2,3-diaminopropionic acid (Bachem, 220 g, 0.923 mol) in MeOH (2 L) at 0° C. was added thionyl chloride (76 mL, 1.04 mol) over 20 min. The solution was warmed to room temperature overnight (18 h) and then concentrated to give a solid. The solid was crystallized from CHCl3 -MeOH to give 172 g (64%) of the desired ester; 1 H NMR (DMSO-d6) δ 8.38 (b, 3H), 7.96 (d, 1H), 7.38 (m, 5H), 5.05 (s, 2H), 4.44 (m, 1H), 3.66 (s, 3H), 3.14 (m, 2H).
Part B: Methyl N2 -Cbz-N3 -Boc-L-2,3-diaminopropionate
To a solution of methyl N2 -Cbz-(S)-2,3-diaminopropionate HCl salt (172 g, 0.596 mol) and di-tert-butyl dicarbonate (129.05 g, 0.591 mol) in CH2 Cl2 (2 L) cooled in an ice bath was added a saturated solution of NaHCO3 (1200 mL, 0.96 mol) and the solution was warmed to room temperature overnight (18 h). The layers were separated and the aqueous washed with CH2 Cl2 (2×500 mL). The combined organic was washed with brine, dried (MgSO4), and concentrated. The resulting white solid was triturated with hexanes (3×500 mL) and dried under vacuum, giving 195.99 g (93%) of the desired material; 1 H NMR (DMSO-d6): δ 7.60 (d, 1H), 7.35 (m, 5H), 6.88 (t, 1H), 5.02 (s, 2H), 4.14 (m, 1H), 3.60 (s, 3H), 3.28 (m, 2H), 1.37 (s, 9H).
Part C: Methyl N3 -Boc-(S)-2,3-diaminopropionate
To a solution of methyl N2 -Cbz-N3 -Boc-(S)-2,3-diaminopropionate. (54.7 g, 0.155 mol) in EtOH (300 mL) was added 10% Pd/C (4.0 g). The mixture was placed on a Parr apparatus and hydrogenated at 50 p.s.i. overnight (18 h). The catalyst was filtered through Celite®, the filter cake washed with EtOH (3×50 mL) and the filtrate was concentrated in vacuo and placed under vacuum to give 32.63 g (96%) of the free base amine as a golden, viscous liquid; 1 H NMR (DMSO-d6): δ 8.20 (s, 1H), 6.90 (t, 1H), 5.36 (b, 3H), 3.61 9s, 3H), 3.51 (t, 1H), 3.18 (t, 2H), 1.38 (s, 9H).
EXAMPLE 2502 Resolution of 3-(4-cyanophenyl)isoxazolin-5(R,S)-ylacetic acid by Crystallization
3-(4-Cyanophenyl)isoxazolin-5(S)-ylacetic acid (127 g, 0.55 moles) and (+)-cinchonidine (180.37 g, 0.55 mol) were added to acetone (2.0 L) and stirred at ambien temperature for at least 1.5 hrs. The resulting precipitate (169.21 g) was collected by filtration. The precipitate was dissolved in hot acetone (4.0 L) while stirring. After complete dissolution, the solution was allowed to stand overnight. The crystals formed were collected by filtration and recrystallized with acetone gain to yield the 3-(4-cyanophenyl)isoxazolin-5(S)-lacetic acid/(+)-cinchonidine salt in 33% overall yield and >99 % diastereomeric excess. The 3-(4-cyanophenyl)isoxazolin-5(S)-ylacetic acid was liberated from its cinchonidine salt complex by suspending the salt in ethereal HCL (1 N), filtering the solid after equilibration and evaporating the ether solution to provide the solid 3-(4-cyanophenyl)isoxazolin-5(S)-ylacetic acid. The R-isomer could be obtained from the mother liquor. Other chiral bases used include ephedrine, 2-phenylglycinol, 2-amino-3-methoxy-1-propanol, quinidine and pseudoephedrine.
EXAMPLE 2503 General Procedure for the Preparation of Compounds of the Formula (Ie) and (If)
Part A.
Z-2,3-diaminopropionic acid (2.5 g, Fluka) was combined with Fmoc-N-Hydroxysuccinimide (1.1 eq., 3.89 g) and NaHCO3 (3 eq., 2.65 g), in dioxane (24 ml) and H2 O (21 ml). After stirring at room temperature overnight, the pH was adjusted with Na2 CO3 to pH 9. The solution was extracted three times with ethyl ether, then the aqueous layer was acidified with conc. HCl, with stirring. At pH 4-5, a solid precipitated out. This was filtered, rinsed with 1 N HCl, and dried. (93% yield)
Part B.
Wang resin (2.0 g, 1.16 mmole/g, Advanced Chem Tech) was added to triphenylphosphine (5 eq, 3.0 g) in 20 ml DMF. CBr4 (5 eq, 3.85 g) was then added and the solution was stirred at room temperature 3 hours. The resin was filtered and rinsed with DMF. Fmoc-Z-2,3-diaminopropionic acid (1.60 g, 1.5 equiv.) was dissolved in 20 ml DMF and the above resin was added, with 1.5 equiv. DIEA (0.60 ml) and 1.0 equiv. CsI (0.60 g) and stirred at room temperature overnight. The resin was filtered and rinsed with DMF and MeOH. Weight gain, IR, elemental analysis, and picric acid determination were used to establish the substitution level of the resin as approx. 0.8 mmole/g.
Part C.
The above derivatized resin (150 mg) was deprotected by mixing 10 min. with 20% piperidine/DMF. of The Fmoc-isoxazolin derivative (1.5 eq., 0.18 mmole) was dissolved in 1.5 ml DMF and added to the resin with HBTU (1.5 eq, 68 mg) and DIEA (1.5 eq, 32 ul). The tubes were mixed overnight, then drained, rinsed with DMF and MeOH, and the resin split into two portions. One portion was deprotected with 20% piperidine/DMF and then cleaved to produce the primary amine analogs. The other portion was deprotected with 20% piperidine/DMF and then coupled overnight with bis Boc-S-ethyl isothiourea (2 eq., 37 mg) and DEA (2 eq., 21 ul) in DMF.
Part D.
After rinsing, the compounds were cleaved from the resin by mixing with 1:1 TFA:CH2 Cl2 for two hours. The filtrate was rotovapped under reduced pressure to an oil, dissolved in 1:1 acetonitrile:H2 O, and lyophilized. The crude material was analyzed by mass spec and HPLC. They were then purified by reverse phase HPLC (ACN:H2 O:0.1% TFA, C 18 column).
Using the above methods and variations thereof known in the art of organic synthesis, the additional examples in Tables 1-2, 2A-2D, 3-14 can be prepared.
                                  TABLE 1                                 
__________________________________________________________________________
                                  (V)                                     
 ##STR65##                                                                
Ex.                                                                       
No.                                                                       
   R.sup.2                                                                
      R.sup.4 Y              n R.sup.14                                   
                                   n'                                     
__________________________________________________________________________
 1 H  H       OH             2 H   0                                      
 2 H  NHSO.sub.2 nC.sub.4 H.sub.9                                         
              OH             2 H   0                                      
 3 H  NHSO.sub.2 CH.sub.2 Ph                                              
              OH             2 H   0                                      
 4 H  NHCO.sub.2 CH.sub.2 Ph                                              
              OH             2 H   0                                      
 5 H  NHCOnC.sub.4 H.sub.9                                                
              OH             2 H   0                                      
 6 H  H       OH             1 H   1                                      
 7 H  H       OH             1 H   0                                      
 8 H  H       OH             2 H   1                                      
 9 H  NHSO.sub.2 nC.sub.4 H.sub.9                                         
              OH             1 H   1                                      
10 H  NHSO.sub.2 CH.sub.2 Ph                                              
              OH             1 H   1                                      
11 H  NHCO.sub.2 CH.sub.2 Ph                                              
              OH             1 H   1                                      
12 H  NHCOnC.sub.4 H.sub.9                                                
              OH             1 H   1                                      
13 H  NHSO.sub.2 nC.sub.4 H.sub.9                                         
              OMe            2 H   0                                      
14 H  NHCO.sub.2 CH.sub.2 Ph                                              
              OMe            2 H   0                                      
15 H  NHSO.sub.2 nC.sub.4 H.sub.9                                         
              CMe            1 H   1                                      
16 H  NHCO.sub.2 CH.sub.2 Ph                                              
              OMe            1 H   1                                      
17 H  NHSO.sub.2 nC.sub.4 H.sub.9                                         
              OEt            2 H   0                                      
18 H  NHCO.sub.2 CH.sub.2 Ph                                              
              OEt            2 H   0                                      
19 H  NHSO.sub.2 nC.sub.4 H.sub.9                                         
              OEt            1 H   1                                      
20 H  NHCO.sub.2 CH.sub.2 Ph                                              
              OEt            1 H   1                                      
21 Boc                                                                    
      NHSO.sub.2 nC.sub.4 H.sub.9                                         
              OH             2 H   0                                      
22 Boc                                                                    
      NHCO.sub.2 CH.sub.2 Ph                                              
              OH             2 H   0                                      
23 Boc                                                                    
      NHSO.sub.2 nC.sub.4 H.sub.9                                         
              OH             1 H   1                                      
24 Boc                                                                    
      NHCO.sub.2 CH.sub.2 Ph                                              
              OH             1 H   1                                      
25 Cbz                                                                    
      NHSO.sub.2 nC.sub.4 H.sub.9                                         
              OH             2 H   0                                      
26 Cbz                                                                    
      NHCO.sub.2 CH.sub.2 Ph                                              
              OH             2 H   0                                      
27 Cbz                                                                    
      NHSO.sub.2 nC.sub.4 H.sub.9                                         
              OH             1 H   1                                      
28 Cbz                                                                    
      NHCO.sub.2 CH.sub.2 Ph                                              
              OH             1 H   1                                      
29 H  NHSO.sub.2 nC.sub.4 H.sub.9                                         
               ##STR66##     2 H   0                                      
30 H  NHSO.sub.2 nC.sub.4 H.sub.9                                         
               ##STR67##     2 H   0                                      
31 H  NHSO.sub.2 nC.sub.4 H.sub.9                                         
               ##STR68##     2 H   0                                      
32 H  NHSO.sub.2 nC.sub.4 H.sub.9                                         
               ##STR69##     2 H   0                                      
31 H  NHSO.sub.2 nC.sub.4 H.sub.9                                         
               ##STR70##     2 H   0                                      
33 H  H       OH             2 CO.sub.2 Me                                
                                   0                                      
34 H  H       OMe            2 H   0                                      
35 H  NHSO.sub.2 CH.sub.2 Ph                                              
              OMe            2 H   0                                      
36 H  NHCOnC.sub.4 H.sub.9                                                
              OMe            2 H   0                                      
37 H  H       OMe            1 H   1                                      
38 H  H       OMe            1 H   0                                      
39 H  H       OMe            2 H   1                                      
40 H  NHSO.sub.2 CH.sub.2 Ph                                              
              OMe            1 H   1                                      
41 H  NHCOnC.sub.4 H.sub.9                                                
              OMe            1 H   1                                      
42 H  H       OMe            2 CO.sub.2 Me                                
                                   0                                      
__________________________________________________________________________

                                  TABLE 2                                 
__________________________________________________________________________
                                       (VI)                               
 ##STR71##                                                                
Example                              MS                                   
Number                                                                    
     R.sup.2                                                              
        R.sup.8       Y              (M + H).sup.+                        
__________________________________________________________________________
 43  H  Ph            OH             412                                  
 .sup.  43A                                                               
     H  Ph            OH             HNMR                                 
 44  H                                                                    
         ##STR72##    OH                                                  
 45  H                                                                    
         ##STR73##    OH                                                  
 46  H                                                                    
         ##STR74##    OH                                                  
 47  H                                                                    
         ##STR75##    OH                                                  
 48  H                                                                    
         ##STR76##    OH                                                  
 49  H                                                                    
         ##STR77##    OH                                                  
 50  H                                                                    
         ##STR78##    OH                                                  
 51  H                                                                    
         ##STR79##    OH                                                  
 52  H                                                                    
         ##STR80##    OH                                                  
 53  H                                                                    
         ##STR81##    OH                                                  
 54  H                                                                    
         ##STR82##    OH                                                  
 55  H                                                                    
         ##STR83##    OH                                                  
 56  H                                                                    
         ##STR84##    OH                                                  
 57  H                                                                    
         ##STR85##    OH                                                  
 58  H                                                                    
         ##STR86##    OH                                                  
 59  H                                                                    
         ##STR87##    OH                                                  
 60  H                                                                    
         ##STR88##    OH                                                  
 61  H                                                                    
         ##STR89##    OH                                                  
 62  H                                                                    
         ##STR90##    OH                                                  
 63  H                                                                    
         ##STR91##    OH                                                  
 64  H                                                                    
         ##STR92##    OH                                                  
 65  H                                                                    
         ##STR93##    OH                                                  
 66  H                                                                    
         ##STR94##    OH                                                  
 67  H                                                                    
         ##STR95##    OH                                                  
 68  H                                                                    
         ##STR96##    OH                                                  
 69  H  Et            OH                                                  
 70  H  n-Pr          OH                                                  
 71  H  --C.tbd.CH    OH                                                  
 72  H  CO.sub.2 H    OH                                                  
 73  H  CH.sub.2 Ph   OH                                                  
 74  H  CH.sub.2 CH.sub.2 Ph                                              
                      OH                                                  
 75  H  --C═CH.sub.2                                                  
                      OH                                                  
 76  H                                                                    
         ##STR97##    OH                                                  
 80  Cbz                                                                  
        Ph            OH                                                  
 81  Cbz                                                                  
         ##STR98##    OH                                                  
 82  Boc                                                                  
        Ph            OH                                                  
 83  Boc                                                                  
         ##STR99##    OH                                                  
 84  H                                                                    
         ##STR100##                                                       
                       ##STR101##                                         
 85  H                                                                    
         ##STR102##                                                       
                       ##STR103##                                         
 86  H                                                                    
         ##STR104##                                                       
                       ##STR105##                                         
 87  H                                                                    
         ##STR106##                                                       
                       ##STR107##                                         
 88  H                                                                    
         ##STR108##                                                       
                       ##STR109##                                         
 89  H  Ph            OMe                                                 
 90  H                                                                    
         ##STR110##   OMe                                                 
 91  H                                                                    
         ##STR111##   OMe                                                 
 92  H                                                                    
         ##STR112##   OMe                                                 
 93  H                                                                    
         ##STR113##   OMe                                                 
 94  H                                                                    
         ##STR114##   OMe                                                 
 95  H                                                                    
         ##STR115##   OMe                                                 
 96  H                                                                    
         ##STR116##   OMe                                                 
 97  H                                                                    
         ##STR117##   OMe                                                 
 98  H                                                                    
         ##STR118##   OMe                                                 
 99  H                                                                    
         ##STR119##   OMe                                                 
100  H                                                                    
         ##STR120##   OMe                                                 
101  H                                                                    
         ##STR121##   OMe                                                 
102  H                                                                    
         ##STR122##   OMe                                                 
103  H                                                                    
         ##STR123##   OMe                                                 
104  H                                                                    
         ##STR124##   OMe                                                 
105  H                                                                    
         ##STR125##   OMe                                                 
106  H                                                                    
         ##STR126##   OMe                                                 
107  H                                                                    
         ##STR127##   OMe                                                 
108  H                                                                    
         ##STR128##   OMe                                                 
109  H                                                                    
         ##STR129##   OMe                                                 
110  H                                                                    
         ##STR130##   OMe                                                 
111  H                                                                    
         ##STR131##   OMe                                                 
112  H                                                                    
         ##STR132##   OMe                                                 
113  H                                                                    
         ##STR133##   OMe                                                 
114  H                                                                    
         ##STR134##   OMe                                                 
115  H  Et            OMe            361                                  
116  H  n-Pr          OMe                                                 
117  H  --C.tbd.H     OMe                                                 
118  H  CO.sub.2 H    OMe                                                 
119  H  CH.sub.2 Ph   OMe            423                                  
120  H  CH.sub.2 CH.sub.2 Ph                                              
                      OMe            437                                  
121  H  --C═CH.sub.2                                                  
                      OMe                                                 
122  H                                                                    
         ##STR135##   OMe                                                 
126  Cbz                                                                  
        Ph            OMe                                                 
127  Cbz                                                                  
         ##STR136##   OMe                                                 
128  Boc                                                                  
        Ph            OMe                                                 
129  Boc                                                                  
         ##STR137##   OMe                                                 
130  H  Ph            OEt                                                 
131  H                                                                    
         ##STR138##   OEt                                                 
132  H                                                                    
         ##STR139##   OEt                                                 
133  H                                                                    
         ##STR140##   OEt                                                 
134  H                                                                    
         ##STR141##   OEt                                                 
135  H                                                                    
         ##STR142##   OEt                                                 
136  H                                                                    
         ##STR143##   OEt                                                 
137  H                                                                    
         ##STR144##   OEt                                                 
138  H                                                                    
         ##STR145##   OEt                                                 
139  H                                                                    
         ##STR146##   OEt                                                 
140  H                                                                    
         ##STR147##   OEt                                                 
141  H                                                                    
         ##STR148##   OEt                                                 
142  H                                                                    
         ##STR149##   OEt                                                 
143  H                                                                    
         ##STR150##   OEt                                                 
144  H                                                                    
         ##STR151##   OEt                                                 
145  H                                                                    
         ##STR152##   OEt                                                 
146  H                                                                    
         ##STR153##   OEt                                                 
147  H                                                                    
         ##STR154##   OEt                                                 
148  H                                                                    
         ##STR155##   OEt                                                 
149  H                                                                    
         ##STR156##   OEt                                                 
150  H                                                                    
         ##STR157##   OEt                                                 
151  H                                                                    
         ##STR158##   OEt                                                 
152  H                                                                    
         ##STR159##   OEt                                                 
153  H                                                                    
         ##STR160##   OEt                                                 
154  H                                                                    
         ##STR161##   OEt                                                 
155  H                                                                    
         ##STR162##   OEt                                                 
156  H  Et            OEt                                                 
157  H  n-Pr          OEt                                                 
158  H  --C═H     OEt                                                 
159  H  CO.sub.2 H    OEt                                                 
160  H  CH.sub.2 Ph   OEt                                                 
161  H  CH.sub.2 CH.sub.2 Ph                                              
                      OEt                                                 
162  H  --C.tbd.CH.sub.2                                                  
                      OEt                                                 
163  H                                                                    
         ##STR163##   OEt                                                 
164  H  CH.sub.2 N(Me)Ph                                                  
                      OEt                                                 
165  H  CH.sub.2 NEt.sub.2                                                
                      OEt                                                 
166  H  CH.sub.2 NMe.sub.2                                                
                      OEt                                                 
167  Cbz                                                                  
        Ph            OEt                                                 
168  Cbz                                                                  
         ##STR164##   OEt                                                 
169  Boc                                                                  
        Ph            OEt                                                 
170  Boc                                                                  
         ##STR165##   OEt                                                 
338  H  CO.sub.2 Me   OMe            mp 160°                       
339  H  CO.sub.2 Me   H              363                                  
340  H  CONMe.sub.2   OMe            404                                  
341  H                                                                    
         ##STR166##   OMe            524                                  
343  H  n-butyl       OH                                                  
344  H  n-butyl       OMe            389                                  
345  H  n-butyl       OEt                                                 
346  H  isobutyl      OH                                                  
347  H  isobutyl      OMe            389                                  
348  H  isobutyl      OEt            403                                  
349  H  CH.sub.2 SPh  OH                                                  
350  H  CH.sub.2 SPh  OMe            455                                  
351  H  CH.sub.2 SPh  OEt                                                 
352  H  CH.sub.2 OPh  OH                                                  
353  H  CH.sub.2 OPh  OMe                                                 
354  H  CH.sub.2 OPh  OEt                                                 
355  H  CH.sub.2 SO.sub.2 Ph                                              
                      OH                                                  
356  H  CH.sub.2 SO.sub.2 Ph                                              
                      OMe                                                 
357  H  CH.sub.2 SO.sub.2 Ph                                              
                      OEt                                                 
358  H  CH.sub.2 NHSO.sub.2 Ph                                            
                      OH                                                  
359  H  CH.sub.2 NHSO.sub.2 Ph                                            
                      OMe            502                                  
360  H  CH.sub.2 NHSO.sub.2 Ph                                            
                      OEt                                                 
361  H  CH.sub.2 NHSO.sub.2 n-Bu                                          
                      OH                                                  
362  H  CH.sub.2 NHSO.sub.2 n-Bu                                          
                      OMe            482                                  
363  H  CH.sub.2 NHSO.sub.2 n-Bu                                          
                      OEt                                                 
364  H  CH.sub.2 COOH OH             377                                  
365  H  CH.sub.2 COOMe                                                    
                      OMe            405                                  
366  H  CH.sub.2 COOEt                                                    
                      OEt                                                 
367  H  CH.sub.2 CH.sub.2 COOH                                            
                      OH                                                  
368  H  CH.sub.2 CH.sub.2 COOMe                                           
                      OMe            419                                  
369  H  CH.sub.2 CH.sub.2 COOEt                                           
                      OEt                                                 
370  H  CH.sub.2 NMe.sub.2                                                
                      OH                                                  
371  H  CH.sub.2 NMe.sub.2                                                
                      OMe            390                                  
372  H  CH.sub.2 NMe.sub.2                                                
                      OEt                                                 
434  BOC                                                                  
        --C(═O)NH--(CH.sub.2).sub.2 C.sub.6 H.sub.5                   
                      OtBu           622                                  
435  H  --C(═O)NH--(CH.sub.2).sub.2 C.sub.6 H.sub.5                   
                      OH             466                                  
439  H  --C(═O)OC.sub.2 H.sub.5                                       
                      OEt            419                                  
441  H                                                                    
         ##STR167##   OH             484                                  
446  H  (CH.sub.2).sub.3 Ph                                               
                      OMe                                                 
447  H  CH.sub.2 -(2-pyr)                                                 
                      OMe                                                 
448  H  (CH.sub.2).sub.2 -(2-pyr)                                         
                      OMe                                                 
449  H  (CH.sub.2).sub.2 -(3-pyr)                                         
                      OMe            438                                  
450  H  (CH.sub.2).sub.2 -(4-pyr)                                         
                      OMe            438                                  
452  H  --C(═O)NH--(CH.sub.2).sub.2 C.sub.6 H.sub.5                   
                      OMe            480                                  
453  BOC                                                                  
         ##STR168##   OMe            635                                  
454  H  C(═O)N(CH.sub.3)--                                            
                      OMe                                                 
        (CH.sub.2).sub.2 C.sub.6 H.sub.5                                  
455  H                                                                    
         ##STR169##   OMe                                                 
456  H  i-hexyl       OEt            431                                  
457  H  --C.tbd.CSiMe.sub.3                                               
                      OMe            429                                  
458  H  --(CH.sub.2).sub.2 -(3-pyr)                                       
                      OH             424                                  
459  H  --(CH.sub.2).sub.2 -(2-pyr)                                       
                      OH             424                                  
460  H  --(CH.sub.2).sub.3 --C.sub.6 H.sub.5                              
                      OH             437                                  
461  H  --(CH.sub.2).sub.3 --C.sub.6 H.sub.5                              
                      OMe            451                                  
462  H                                                                    
         ##STR170##   OEt            538                                  
463  H                                                                    
         ##STR171##   OH             510                                  
464  H                                                                    
         ##STR172##   OMe            492                                  
465  H                                                                    
         ##STR173##   OMe            492                                  
466  H                                                                    
         ##STR174##   OMe            510                                  
467  H                                                                    
         ##STR175##   OMe            510                                  
468  H                                                                    
         ##STR176##   OMe            462                                  
469  H                                                                    
         ##STR177##   OMe            448                                  
587  H  --(CH.sub.2).sub.3 -(4-pyr)                                       
                      OH             424                                  
611  H  --CH.sub.2 NHSO.sub.2 NMe.sub.2                                   
                      OMe            469                                  
612  H                                                                    
         ##STR178##   OMe            416                                  
__________________________________________________________________________

                                  TABLE 2A                                
__________________________________________________________________________
Example                          MS                                       
Number                                                                    
     R.sup.1 -V   R.sup.16   Y   (M + H).sup.+                            
__________________________________________________________________________
275  4-amidinophenyl                                                      
                  H          OH  334                                      
276  4-amidinophenyl                                                      
                  benzyloxycarbonyl                                       
                             OH  468                                      
277  4-amidinophenyl                                                      
                  t-butyloxycarbonyl                                      
                             OH                                           
278  4-amidinophenyl                                                      
                  n-butyloxycarbonyl                                      
                             OH  434                                      
278a 4-amidinophenyl                                                      
                  n-butyloxycarbonyl                                      
                             OMe 448                                      
278b 4-amidinophenyl                                                      
                  n-butyloxycarbonyl                                      
                             OH  434                                      
279  4-amidinophenyl                                                      
                  ethyloxycarbonyl                                        
                             OH                                           
280  4-amidinophenyl                                                      
                  methyloxycarbonyl                                       
                             OH                                           
290  4-amidinophenyl                                                      
                  phenylethylcarbonyl                                     
                             OH  510                                      
291  4-amidinophenyl                                                      
                  2,2-dimethyl-                                           
                             OH                                           
                  propyl carbonyl                                         
292  4-amidinophenyl                                                      
                  n-pentylcarbonyl                                        
                             OH                                           
293  4-amidinophenyl                                                      
                  n-butylcarbonyl                                         
                             OH                                           
294  4-amidinophenyl                                                      
                  propionyl  OH                                           
295  4-amidinophenyl                                                      
                  acetyl     OH                                           
296  4-amidinophenyl                                                      
                  methylsulfonyl                                          
                             OH                                           
297  4-amidinophenyl                                                      
                  ethylsulfonyl                                           
                             OH                                           
298  4-amidinophenyl                                                      
                  n-butylsulfonyl                                         
                             OH                                           
299  4-amidinophenyl                                                      
                  phenylsulfonyl                                          
                             OH  474                                      
300  4-amidinophenyl                                                      
                  4-methylphenyl-                                         
                             OH  488                                      
                  sulfonyl                                                
301  4-amidinophenyl                                                      
                  benzylsulfonyl                                          
                             OH                                           
302  4-amidinophenyl                                                      
                  2-pyridylcarbonyl                                       
                             OH                                           
303  4-amidinophenyl                                                      
                  3-pyridylcarbonyl                                       
                             OH                                           
304  4-amidinophenyl                                                      
                  4-pyridylcarbonyl                                       
                             OH                                           
305  4-amidinophenyl                                                      
                  2-pyridylmethyl-                                        
                             OH                                           
                  carbonyl                                                
306  4-amidinophenyl                                                      
                  3-pyridylmethyl                                         
                             OH                                           
                  carbonyl                                                
307  4-amidinophenyl                                                      
                  4-pyridylmethyl-                                        
                             OH                                           
                  carbonyl                                                
308  4-amidinophenyl                                                      
                  2-pyridylmethoxy-                                       
                             OH                                           
                  carbonyl                                                
309  4-amidinophenyl                                                      
                  3-pyridylmethoxy-                                       
                             OH                                           
                  carbonyl                                                
310  4-amidinophenyl                                                      
                  4-pyridylmethoxy-                                       
                             OH                                           
                  carbonyl                                                
311  4-amidinophenyl                                                      
                  H          OMe                                          
312  4-amidinophenyl                                                      
                  benzyloxycarbonyl                                       
                             OMe 482                                      
313  4-amidinophenyl                                                      
                  t-butyloxycarbonyl                                      
                             OMe                                          
314  4-amidinophenyl                                                      
                  n-butyloxycarbonyl                                      
                             OMe 448                                      
315  4-amidinophenyl                                                      
                  ethyloxycarbonyl                                        
                             OMe                                          
316  4-amidinophenyl                                                      
                  methyloxycarbonyl                                       
                             OMe                                          
317  4-amidinophenyl                                                      
                  phenylethylsulfonyl                                     
                             OH  502                                      
318  4-amidinophenyl                                                      
                  2,2-dimethyl-                                           
                             OMe                                          
                  propylcarbonyl                                          
319  4-amidinophenyl                                                      
                  n-pentylcarbonyl                                        
                             OMe                                          
320  4-amidinophenyl                                                      
                  n-butylcarbonyl                                         
                             OMe                                          
321  4-amidinophenyl                                                      
                  propionyl  OMe                                          
322  4-amidinophenyl                                                      
                  acetyl     OMe                                          
323  4-amidinophenyl                                                      
                  methylsulfonyl                                          
                             OMe 426                                      
324  4-amidinophenyl                                                      
                  ethylsulfonyl                                           
                             OMe 440                                      
325  4-amidinophenyl                                                      
                  n-butylsulfonyl                                         
                             OMe                                          
326  4-amidinophenyl                                                      
                  phenylsulfonyl                                          
                             OMe 488                                      
327  4-amidinophenyl                                                      
                  4-methylphenyl-                                         
                             OMe 502                                      
                  sulfonyl                                                
328  4-amidinophenyl                                                      
                  benzylsulfonyl                                          
                             OMe 502                                      
329  4-amidinophenyl                                                      
                  2-pyridylcarbonyl                                       
                             OMe                                          
330  4-amidinophenyl                                                      
                  3-pyridylcarbonyl                                       
                             OMe                                          
331  4-amidinophenyl                                                      
                  4-pyridylcarbonyl                                       
                             OMe                                          
332  4-amidinophenyl                                                      
                  2-pyridylmethyl-                                        
                             OMe                                          
                  carbonyl                                                
333  4-amidinophenyl                                                      
                  3-pyridylmethyl-                                        
                             OMe                                          
                  carbonyl.                                               
334  4-amidinophenyl                                                      
                  4-pyridylmethyl-                                        
                             OMe                                          
                  carbonyl                                                
335  4-amidinophenyl                                                      
                  2-pyridylmethoxy-                                       
                             OMe                                          
                  carbonyl                                                
336  4-amidinophenyl                                                      
                  3-pyridylmethoxy-                                       
                             OMe                                          
                  carbonyl                                                
337  4-amidinophenyl                                                      
                  4-pyridylmethoxy-                                       
                             OMe                                          
                  carbonyl                                                
374                                                                       
      ##STR179##  benzyloxycarbonyl                                       
                             OMe 475                                      
440  4-(BOCamidino)phenyl                                                 
                  benzyloxycarbonyl                                       
                             OMe 582                                      
442  4-(BOCamidino)phenyl                                                 
                  n-butyloxycarbonyl                                      
                             OMe 594                                      
443  4-amidinophenyl                                                      
                  1-naphthylsulfonyl                                      
                             OMe 538                                      
444  4-amidinophenyl                                                      
                  2-naphthylsulfonyl                                      
                             OMe 538                                      
445  4-amidinophenyl                                                      
                  styrylsulfonyl                                          
                             OMe 514                                      
445a 4-amidinophenyl                                                      
                  styrylsulfonyl                                          
                             OH  500                                      
451                                                                       
      ##STR180##  n-butyloxycarbonyl                                      
                             OMe 441                                      
471  4-amidinophenyl                                                      
                  4-butyloxyphenyl-                                       
                             OMe 560                                      
                  sulfonyl                                                
472  4-amidinophenyl                                                      
                  2-thienylsulfonyl                                       
                             OMe 494                                      
473  4-amidinophenyl                                                      
                  3-methylphenyl-                                         
                             OMe 502                                      
                  sulfonyl                                                
474  4-amidinophenyl                                                      
                  4-iodophenyl                                            
                             OMe 614                                      
475  4-amidinophenyl                                                      
                  3-trifluoromethyl-                                      
                             OMe 556                                      
                  phenylsulfonyl                                          
476  4-amidinophenyl                                                      
                  3-chlorophenyl-                                         
                             OMe 522                                      
                  sulfonyl                                                
477  4-amidinophenyl                                                      
                  2-methoxycarbonyl-                                      
                             OMe 546                                      
                  phenylsulfonyl                                          
478  4-amidinophenyl                                                      
                  2,4,6-trimethyl-                                        
                             OMe 530                                      
                  phenylsulfonyl                                          
478a 4-amidinophenyl                                                      
                  2,4,6-trimethyl-                                        
                             OH  516                                      
                  phenylsulfonyl                                          
479  4-amidinophenyl                                                      
                  2-chlorophenyl-                                         
                             OMe 522                                      
                  sulfonyl                                                
479a 4-amidinophenyl                                                      
                  2-chlorophenyl-                                         
                             OH  508                                      
                  sulfonyl                                                
480  4-amidinophenyl                                                      
                  2-trifluoromethyl-                                      
                             OMe 556                                      
                  phenylsulfonyl                                          
481  4-amidinophenyl                                                      
                  4-trifluoromethyl-                                      
                             OMe 556                                      
                  phenylsulfonyl                                          
482  4-amidinophenyl                                                      
                  2-fluorophenyl-                                         
                             OMe 506                                      
                  sulfonyl                                                
483  4-amidinophenyl                                                      
                  4-fluorophenyl-                                         
                             OMe 506                                      
                  sulfonyl                                                
484  4-amidinophenyl                                                      
                  4-methoxyphenyl-                                        
                             OMe 518                                      
                  sulfonyl                                                
485  4-amidinophenyl                                                      
                  2,3,5,6-tetramethyl-                                    
                             OMe 544                                      
                  phenylsulfonyl                                          
485a 4-amidinophenyl                                                      
                  2,3,5,6-tetramethyl-                                    
                             OH  530                                      
                  phenylsulfonyl                                          
486  4-amidinophenyl                                                      
                  4-cyanophenyl-                                          
                             OMe 513                                      
                  sulfonyl                                                
487  4-amidinophenyl                                                      
                  4-chlorophenyl-                                         
                             OMe 522                                      
                  sulfonyl                                                
488  4-amidinophenyl                                                      
                  4-ethylphenyl-                                          
                             OMe 516                                      
                  sulfonyl                                                
489  4-amidinophenyl                                                      
                  4-propylphenyl-                                         
                             OMe 530                                      
                  sulfonyl                                                
490  4-amidinophenyl                                                      
                  n-propylsulfonyl                                        
                             OMe 454                                      
490a 4-amidinophenyl                                                      
                  n-propylsulfonyl                                        
                             OH  440                                      
491  4-amidinophenyl                                                      
                  2-phenylethyl-                                          
                             OMe 516                                      
                  sulfonyl                                                
492  4-amidinophenyl                                                      
                  4-isopropylphenyl-                                      
                             OMe 530                                      
                  sulfonyl                                                
492a 4-amidinophenyl                                                      
                  4-isopropylphenyl-                                      
                             OH  516                                      
                  sulfonyl                                                
493  4-amidinophenyl                                                      
                  3-phenylpropyl-                                         
                             OMe 530                                      
                  sulfonyl                                                
494  4-amidinophenyl                                                      
                  3-pyridylsulfonyl                                       
                             OMe 489                                      
495  4-amidinophenyl                                                      
                  2-pyridylsulfonyl                                       
                             OMe 489                                      
496  4-amidinophenyl                                                      
                  2,2-diphenyl-1-                                         
                             OMe 590                                      
                  ethenylsulfonyl                                         
497  4-amidinophenyl                                                      
                  2-pyrimidinyl-                                          
                             OMe                                          
                  sulfonyl                                                
498  4-amidinophenyl                                                      
                  4-methyl-2-                                             
                             OMe                                          
                  pyrimidinylsulfonyl                                     
499  4-amidinophenyl                                                      
                  4,6-dimethyl-2-                                         
                             OMe                                          
                  pyrimidinylsulfonyl                                     
500  4-amidinophenyl                                                      
                  1,2,4-triazol-3-                                        
                             OMe                                          
                  ylsulfonyl                                              
501  4-amidinophenyl                                                      
                  1-methyl-1,3,4-                                         
                             OMe                                          
                  triazol-5-ylsulfonyl                                    
502  4-amidinophenyl                                                      
                  3,5-dimethyl-4-                                         
                             OMe                                          
                  pyrazolylsulfonyl                                       
503  4-amidinophenyl                                                      
                  1-phenyl-4-                                             
                             OMe                                          
                  pyrazolylsulfonyl                                       
504  4-amidinophenyl                                                      
                  n-butylaminosulfonyl                                    
                             OMe 483                                      
505  4-amidinophenyl                                                      
                  i-butylaminosulfonyl                                    
                             OMe 483                                      
506  4-amidinophenyl                                                      
                  t-butylaminosulfonyl                                    
                             OMe 483                                      
507  4-amidinophenyl                                                      
                  i-propylamino-                                          
                             OMe 469                                      
                  sulfonyl                                                
508  4-amidinophenyl                                                      
                  cyclohexylamino-                                        
                             OMe 509                                      
                  sulfonyl                                                
509  4-amidinophenyl                                                      
                  phenylaminosulfonyl                                     
                             OMe 503                                      
510  4-amidinophenyl                                                      
                  benzylaminosulfonyl                                     
                             OMe 517                                      
511  4-amidinophenyl                                                      
                  dimethylamino-                                          
                             OMe 455                                      
                  sulfonyl                                                
512  4-amidino-2-fluoro-                                                  
                  3-methylphenyl-                                         
                             OMe 520                                      
     phenyl       sulfonyl                                                
512A 4-amidino-2-fluoro-                                                  
                  3-methylphenylsulfonyl                                  
                             OH  506                                      
     phenyl                                                               
514  2-amidino-5-pyridyl                                                  
                  3-methylphenyl-                                         
                             OMe 503                                      
                  sulfonyl                                                
514A 2-amidino-5-pyridyl                                                  
                  3-methylphenylsulfonal                                  
                             OH  489                                      
516  3-amidino-6-pyridyl                                                  
                  3-methylphenyl-                                         
                             OMe 503                                      
                  sulfonyl                                                
516A 3-amidino-6-pyridyl                                                  
                  3-methylphenylsulfonyl                                  
                             OH  489                                      
518  4-amidinophenyl                                                      
                  4-fluorophenylamino-                                    
                             OMe 485                                      
                  carbonyl                                                
519  4-amidinophenyl                                                      
                  1-naphthylamino-                                        
                             OMe 517                                      
                  carbonyl                                                
520  4-amidinophenyl                                                      
                  benzylaminocarbonyl                                     
                             OMe                                          
521  4-amidinophenyl                                                      
                  n-butylaminocarbonyl                                    
                             OMe 435                                      
522  4-amidinophenyl                                                      
                  4-ethylphenyl-                                          
                             OMe 480                                      
                  carbonyl                                                
523  4-amidinophenyl                                                      
                  biphenylcarbonyl                                        
                             OMe 528                                      
524  4-amidinophenyl                                                      
                  2-naphthylcarbonyl                                      
                             OMe 502                                      
525  4-amidinophenyl                                                      
                  (2-chlorophenyl)                                        
                             OMe 516                                      
                  methoxycarbonyl                                         
526  4-amidinophenyl                                                      
                  (2-chlorophenyl)                                        
                             OH  502                                      
                  methoxycarbonyl                                         
527  4-amidinophenyl                                                      
                  (2-bromophenyl)                                         
                             OMe 562                                      
                  methoxycarbonyl                                         
528  4-ainidinophenyl                                                     
                  (2-bromophenyl)                                         
                             OH  548                                      
                  methoxycarbonyl                                         
528a 4-amidinophenyl                                                      
                  (2-bromophenyl)-                                        
                             OH  516                                      
                  carbonyl                                                
529  4-amidinophenyl                                                      
                  n-hexyloxycarbonyl                                      
                             OMe 476                                      
530  4-amidinophenyl                                                      
                  n-hexyloxycarbonyl                                      
                             OH  460                                      
531  4-amidinophenyl                                                      
                  isobutyloxycarbonyl                                     
                             OMe 448                                      
532  4-amidinophenyl                                                      
                  isobutyloxycarbonyl                                     
                             OH  434                                      
533  4-amidinophenyl                                                      
                  2-cyclopropylethoxy-                                    
                             OMe 460                                      
                  carbonyl                                                
534  4-amidinophenyl                                                      
                  2-cyclopropylethoxy-                                    
                             OH  446                                      
                  carbonyl                                                
535  4-amidinophenyl                                                      
                  2-cyclopentylethoxy-                                    
                             OMe 488                                      
                  carbonyl                                                
536  4-amidinophenyl                                                      
                  2-cyclopentylethoxy-                                    
                             OH  474                                      
                  carbonyl                                                
537  4-amidinophenyl                                                      
                  4,4,4-trifluoro-                                        
                             OMe 502                                      
                  butyloxycarbonyl                                        
538  4-amidinophenyl                                                      
                  4,4,4-trifluoro-                                        
                             OH  488.                                     
                  butyloxycarbonyl                                        
539  4-amidinophenyl                                                      
                  n-propylsulfonyl                                        
                             OMe                                          
540  4-amidinophenyl                                                      
                  2-methylphenyl-                                         
                             OH  452                                      
                  carbonyl                                                
540a 4-amidinophenyl                                                      
                  2-methylphenyl-                                         
                             OH  488                                      
                  sulfonyl                                                
541  4-amidinophenyl                                                      
                  4-chloro-2,5-dimethyl-                                  
                             OMe 550                                      
                  phenylsulfonyl                                          
541a 4-amidinophenyl                                                      
                  4-chloro-2,5-dimethyl-                                  
                             OMe 536                                      
                  phenylsulfonyl                                          
542  4-amidinophenyl                                                      
                  2,3-dichlorophenyl-                                     
                             OMe 556                                      
                  sulfonyl                                                
543  4-amidinophenyl                                                      
                  2-bromophenyl-                                          
                             OMe 568                                      
                  sulfonyl                                                
544  4-amidinophenyl                                                      
                  3-bromophenyl-                                          
                             OMe 568                                      
                  sulfonyl                                                
545  4-amidinophenyl                                                      
                  4-bromophenyl-                                          
                             OMe 568                                      
                  sulfonyl                                                
546  4-amidinophenyl                                                      
                  biphenylsulfonyl                                        
                             OMe 564                                      
547  4-amidinophenyl                                                      
                  5-chloro-1,3-                                           
                             OMe 540                                      
                  dimethyl-4-pyrazolyl                                    
548  4-amidinophenyl                                                      
                  3-bromo-2- OMe 574                                      
                  thienylsulfonyl                                         
549  4-amidinophenyl                                                      
                  5-bromo-2- OMe 574                                      
                  thienylsulfonyl                                         
550  4-amidinophenyl                                                      
                  5-[1-methyl-5-                                          
                             OMe 642                                      
                  trifluoromethyl-3-                                      
                  pyrazolyl]-2-                                           
                  thienylsulfonyl                                         
551  4-amidinophenyl                                                      
                  5-(3-isoxazolyl)-2-                                     
                             OMe 561                                      
                  thienylsulfonyl                                         
552  4-amidinophenyl                                                      
                  5-(2-pyridinyl)-2-                                      
                             OMe 571                                      
                  thienylsulfonyl                                         
553  4-amidinophenyl                                                      
                  4-methyl-2-                                             
                             OMe 566                                      
                  methylcarbonylamino-5-                                  
                  thiazolylsulfonyl                                       
554  4-amidinophenyl                                                      
                  2-benzothienyl-                                         
                             OMe 628                                      
                  sulfonyl                                                
555  4-amidinophenyl                                                      
                  2-benzothienyl-                                         
                             OMe 544                                      
                  sulfonyl                                                
556  4-amidinophenyl                                                      
                  3-methyl-2-                                             
                             OMe 558                                      
                  benzothienylsulfonyl                                    
557  4-amidinophenyl                                                      
                  8-quinolinylsulfonyl                                    
                             OMe 539                                      
558  4-amidinophenyl                                                      
                  8-quinolinylsulfonyl                                    
                             OH  525                                      
559  4-amidinophenyl                                                      
                  2,1,3-benzo-                                            
                             OMe 546                                      
                  thiadiazol-4-ylsulfonyl                                 
560  4-amidinophenyl                                                      
                  2,1,3-benzo-                                            
                             OH  532                                      
                  thiadiazol-4-ylsulfonyl                                 
561  4-amidinophenyl                                                      
                  4-N,N-dimethylamino-1-                                  
                             OMe                                          
                  naphthylsulfonyl                                        
562  4-amidinophenyl                                                      
                  4-N,N-dimethylamino-1-                                  
                             OH                                           
                  naphthylsulfonyl                                        
563  4-amidinophenyl                                                      
                  2,1,3-benzoxadiazol-4-                                  
                             OMe                                          
                  ylsulfonyl                                              
564  4-amidinophenyl                                                      
                  2,1,3-benzoxadiazol-4-                                  
                             OH                                           
                  ylsulfonyl                                              
565  4-amidinophenyl                                                      
                  2,2,5,7,8-pentamethyl                                   
                             OMe                                          
                  3,4-dihydro-2Hbenzo-                                    
                  pyran-6-ylsulfonyl                                      
566  4-amidinophenyl                                                      
                  2,2,5,7,8-pentamethyl                                   
                             OH                                           
                  3,4-dihydro-2Hbenzo-                                    
                  pyran-6-ylsulfonyl                                      
567  4-N-methylamidino                                                    
                  3-methylphenylsulfonyl                                  
                             OMe                                          
     phenyl                                                               
568  4-N-ethylamidino                                                     
                  3-methylphenylsulfonyl                                  
                             OMe 530                                      
     phenyl                                                               
569  4-N-n-propylamidino                                                  
                  3-methylphenylsulfonyl                                  
                             OMe                                          
     phenyl                                                               
570  4-N-benzylamidino phenyl                                             
                  3-methylphenylsulfonyl                                  
                             OMe                                          
571  4-N-n-butylamidino                                                   
                  3-methylphenylsulfonyl                                  
                             OMe 558                                      
     phenyl                                                               
572  4-N-methylamidino                                                    
                  3-methylphenylsulfonyl                                  
                             OH                                           
     phenyl                                                               
573  4-N-ethylamidino                                                     
                  3-methylphenylsulfonyl                                  
                             OH  516                                      
     phenyl                                                               
574  4-N-n-propylamidino                                                  
                  3-methylphenylsulfonyl                                  
                             OH                                           
     phenyl                                                               
575  4-N-benzylamidino                                                    
                  3-methylphenylsulfonyl                                  
                             OH                                           
     phenyl                                                               
576  4-N-n-butylamidino                                                   
                  3-methylphenylsulfonyl                                  
                             OH  544                                      
     phenyl                                                               
577  4-N-methylamidino-                                                   
                  n-butyloxycarbonyl                                      
                             OMe                                          
     phenyl                                                               
578  4-N-ethylamidinophenyl                                               
                  n-butyloxycarbonyl                                      
                             OMe                                          
579  4-N-npropylamidino-                                                  
                  n-butyloxycarbonyl                                      
                             OMe                                          
     phenyl                                                               
580  4-N-n-butylamidino-                                                  
                  n-butyloxycarbonyl                                      
                             OMe 504                                      
     phenyl                                                               
581  4-N-benzylamidino-                                                   
                  n-butyloxycarbonyl                                      
                             OMe                                          
     phenyl                                                               
582  4-N-methylamidino-                                                   
                  n-butyloxycarbonyl                                      
                             OH                                           
     phenyl                                                               
583  4-N-ethylamidino-                                                    
                  n-butyloxycarbonyl                                      
                             OH                                           
     phenyl                                                               
584  4-N-n-propylamidino-                                                 
                  n-butyloxycarbonyl                                      
                             OH                                           
     phenyl                                                               
585  4-N-n-butylamidino-                                                  
                  n-butyloxycarbonyl                                      
                             OH                                           
     phenyl                                                               
586  4-N-benzylamidino-                                                   
                  n-butyloxycarbonyl                                      
                             OH                                           
     phenyl                                                               
589  4-(acetoxyamidino)-                                                  
                  n-butyloxycarbonyl                                      
                             OMe                                          
     phenyl                                                               
590  4-(acetoxyamidino)-                                                  
                  n-butyloxycarbonyl                                      
                             OH                                           
     phenyl                                                               
591  4-(acetoxyamidino)-                                                  
                  isobutyloxycarbonyl                                     
                             OMe                                          
     phenyl                                                               
592  4-(acetoxyamidino)                                                   
                  isobutyloxycarbonyl                                     
                             OH                                           
     phenyl                                                               
593  4-(acetoxyamidino)-                                                  
                  cyclopropylethoxy-                                      
                             OMe                                          
     phenyl       carbonyl                                                
594  4-(acetoxyamidino)-                                                  
                  cyclopropylethoxy-                                      
                             OH                                           
     phenyl       carbonyl                                                
595  4-(acetoxyamidino)-                                                  
                  benzyloxycarbonyl                                       
                             OMe                                          
     phenyl                                                               
596  4-(acetoxyamidino)-                                                  
                  benzyloxycarbonyl                                       
     phenyl                                                               
597  4-(acetoxyamidino)-                                                  
                  4-methylphenylsulfonyl                                  
                             OMe                                          
     phenyl                                                               
598  4-(acetoxyamidino)-                                                  
                  4-methylphenylsulfonyl                                  
                             OH                                           
     phenyl                                                               
599  4-(acetoxyamidino)-                                                  
                  3-methylphenylsulfonyl                                  
                             OMe                                          
     phenyl                                                               
600  4-(acetoxyamidino)-                                                  
                  3-methylphenylsulfonyl                                  
                             OH                                           
     phenyl                                                               
601  4-guanidinophenyl                                                    
                  n-butyloxycarbonyl                                      
                             OH                                           
602  4-guanidinophenyl                                                    
                  n-butyloxycarbonyl                                      
                             OMe 463                                      
603  4-guanidinophenyl                                                    
                  benzyloxycarbonyl                                       
                             OH                                           
604  4-guanidinophenyl                                                    
                  benzyloxycarbonyl                                       
                             OMe                                          
605  4-guanidinophenyl                                                    
                  4-methylphenylsulfonyl                                  
                             OH  503                                      
606  4-guanidinophenyl                                                    
                  4-methylphenylsulfonyl                                  
                             OMe 517                                      
607  4-guanidinophenyl                                                    
                  3-methylphenylsulfonyl                                  
                             OH                                           
608  4-guanidinophenyl                                                    
                  3-methylphenylsulfonyl                                  
                             OMe                                          
609  4-guanidinophenyl                                                    
                  n-butylsulfonyl                                         
                             OH                                           
610  4-guanidinophenyl                                                    
                  n-butylsulfonyl                                         
                             OMe                                          
613  4-amidino-2-fluoro-                                                  
                  n-butyloxycarbonyl                                      
                             OMe 466                                      
     phenyl                                                               
614  4-piperidinyl                                                        
                  n-butyloxycarbonyl                                      
                             OMe 412                                      
615  4-piperidinylmethyl                                                  
                  n-butyloxycarbonyl                                      
                             OMe 426                                      
616  4-piperidinylpropyl                                                  
                  n-butyloxycarbonyl                                      
                             OMe 454                                      
617  4-quanidinophenyl                                                    
                  n-butyloxycarbonyl                                      
                             OH  449                                      
618  4-amidinophenylmethyl                                                
                  benzyloxycarbonyl                                       
                             OMe                                          
619  4-amidinophenylmethyl                                                
                  benzyloxycarbonyl                                       
                             OH                                           
220  4-amidinophenylmethyl                                                
                  n-butyloxycarbonyl                                      
                             OMe                                          
621  4-amidinophenylmethyl                                                
                  n-butyloxycarbonyl                                      
                             OH                                           
622  4-amidinophenylmethyl                                                
                  cyclopropylethoxy                                       
                             OMe                                          
                  carbonyl                                                
623  4-amidinophenylmethyl                                                
                  cyclopropylethoxy                                       
                             OH                                           
                  carbonyl                                                
624  4-amidinophenylmethyl                                                
                  4-methylphenylsulfonyl                                  
                             OMe                                          
625  4-amidinophenylmethyl                                                
                  4-methylphenylsulfonyl                                  
                             OH  488                                      
626  4-amidinophenylmethyl                                                
                  3-methylphenylsulfonyl                                  
                             OMe                                          
627  4-amidinophenylmethyl                                                
                  3-methylphenylsulfonyl                                  
                             OH                                           
628  4-amidinophenylmethyl                                                
                  n-butylsulfonyl                                         
                             OMe                                          
629  4-amidinophenylmethyl                                                
                  n-butylsulfonyl                                         
                             OH                                           
630  4-amidinophenylmethoxy                                               
                  benzyloxycarbonyl                                       
                             OMe                                          
631  4-amidinophenylmethoxy                                               
                  benzyloxycarbonyl                                       
                             OH                                           
632  4-amidinophenylmethoxy                                               
                  n-butyloxycarbonyl                                      
                             OMe                                          
633  4-amidinophenylmethoxy                                               
                  n-butyloxycarbonyl                                      
                             OH                                           
634  4-amidinophenylmethoxy                                               
                  cyclopropylethoxy                                       
                             OMe                                          
                  carbonyl                                                
635  4-amidinophenylmethoxy                                               
                  cyclopropylethoxy                                       
                             OH                                           
                  carbonyl                                                
636  4-amidinophenylmethoxy                                               
                  4-methylphenylsulfonyl                                  
                             OMe                                          
637  4-amidinophenylmethoxy                                               
                  4-methylphenylsulfonyl                                  
                             OH                                           
638  4-amidinophenylmethoxy                                               
                  3-methylphenylsulfonyl                                  
                             OMe                                          
639  4-amidinophenylmethoxy                                               
                  3-methylphenylsulfonyl                                  
                             OH                                           
640  4-amidinophenylmethoxy                                               
                  n-butylsulfonyl                                         
                             OMe                                          
641  4-amidinophenylmethoxy                                               
                  n-butylsulfonyl                                         
                             OH                                           
642  4-amidinophenyl                                                      
                  5-chloro-1,3-                                           
                             OMe 526                                      
                  dimethyl-4-pyrazolyl                                    
643  4-amidinophenyl                                                      
                  1-methylimidazol-4-                                     
                             OH  478                                      
                  ylsulfonyl                                              
644  4-amidinophenyl                                                      
                  3,5-dimethyl-1,3-                                       
                             OH  509                                      
                  thioimidazole-2-                                        
                  ylsulfonyl                                              
645  N-t-butyloxycarbonyl-4-                                              
                  5-(2-pyridinyl)-2-                                      
                             OMe 671                                      
     amidinophenyl                                                        
                  thienylsulfonyl                                         
646  N-t-butyloxycarbonyl-4-                                              
                  3,5-dimethyl-1,3                                        
                             OMe 623                                      
     amidinophenyl                                                        
                  thioimidazole-2-                                        
                  ylsulfonyl                                              
647  N-t-butyloxycarbonyl-                                                
                  3,5-dimethylisoxazol-                                   
                             OMe 607                                      
     4-amidinophenyl                                                      
                  4-ylsulfonyl                                            
     TFA salt, 5(R),N.sup.2 (S)                                           
     isomer                                                               
__________________________________________________________________________

                                  TABLE 2B                                
__________________________________________________________________________
 ##STR181##                                                               
Example                          MS                                       
Number                                                                    
     R.sup.1 -V                                                           
             R.sup.5a                                                     
                  R.sup.16    Y  (M + H).sup.+                            
__________________________________________________________________________
651  4-amidinophenyl                                                      
             methyl                                                       
                  benzyloxycarbony                                        
                              OMe                                         
                                 496                                      
652  4-amidinophenyl                                                      
             methyl                                                       
                  n-butyloxycarbony                                       
                              OMe                                         
653  4-amidinophenyl                                                      
             methyl                                                       
                  3-methylphenylsulfonyl                                  
                              OMe                                         
654  4-amidinophenyl                                                      
             methyl                                                       
                  benzyloxycarbonyl                                       
                              OH                                          
655  4-amidinophenyl                                                      
             methyl                                                       
                  n-butyloxycarbonyl                                      
                              OH                                          
656  4-amidinophenyl                                                      
             methyl                                                       
                  3-methylphenylsulfonyl                                  
                              OH                                          
657  4-amidinophenyl                                                      
             methyl                                                       
                  4-methylphenylsulfonyl                                  
                              OH                                          
658  4-amidinophenyl                                                      
             methyl                                                       
                  4-methylphenylsulfonyl                                  
                              OMe                                         
659  4-amidinophenyl                                                      
             methyl                                                       
                  n-butylsulfonyl                                         
                              OH                                          
660  4-amidinophenyl                                                      
             methyl                                                       
                  n-butylsulfonyl                                         
                              OMe                                         
__________________________________________________________________________

                                  TABLE 2C                                
__________________________________________________________________________
 ##STR182##                                                               
Example                         MS                                        
Number                                                                    
     R.sup.1 -V                                                           
              R.sup.16   R.sup.17                                         
                             Y  (M + H).sup.+                             
__________________________________________________________________________
661  4-amidinophenyl                                                      
              benzyloxycarbonyl                                           
                         methyl                                           
                             OMe                                          
662  4-amidinophenyl                                                      
              benzyloxycarbonyl                                           
                         methyl                                           
                             OH                                           
663  4-amidinophenyl                                                      
              n-butyloxycarbonyl                                          
                         methyl                                           
                             OMe                                          
664  4-amidinophenyl                                                      
              n-butyloxycarbonyl                                          
                         methyl                                           
                             OH                                           
665  4-amidinophenyl                                                      
              3-methylphenylsulfonyl                                      
                         methyl                                           
                             OMe                                          
666  4-amidinophenyl                                                      
              3-methylphenylsulfonyl                                      
                         methyl                                           
                             OH 502                                       
667  4-amidinophenyl                                                      
              4-methylphenylsulfonyl                                      
                         methyl                                           
                             OMe                                          
668  4-amidinophenyl                                                      
              4-methylphenylsulfonyl                                      
                         methyl                                           
                             OH                                           
669  4-amidinophenyl                                                      
              n-butylsulfonyl                                             
                         methyl                                           
                             OMe                                          
670  4-amidinophenyl                                                      
              n-butylsulfonyl                                             
                         methyl                                           
                             OH                                           
__________________________________________________________________________

              TABLE 2D                                                    
______________________________________                                    
 ##STR183##                                                               
Example                               MS                                  
Number R.sup.1 --V  R.sup.16     Y    (M +  H).sup.+                      
______________________________________                                    
701    4-amidinophenyl                                                    
                    benzyloxycarbonyl                                     
                                 OH                                       
702    4-amidinophenyl                                                    
                    t-butyloxycarbonyl                                    
                                 OH                                       
703    4-amidinophenyl                                                    
                    n-butyloxycarbonyl                                    
                                 OH                                       
704    4-amidinophenyl                                                    
                    ethyloxycarbonyl                                      
                                 OH                                       
705    4-amidinophenyl                                                    
                    methyloxycarbonyl                                     
                                 OH                                       
706    4-amidinophenyl                                                    
                    phenylethylcarbonyl                                   
                                 OH                                       
707    4-amidinophenyl                                                    
                    2,2-dimethyl-                                         
                                 OH                                       
                    propylcarbonyl                                        
708    4-amidinophenyl                                                    
                    n-pentylcarbonyl                                      
                                 OH                                       
709    4-amidinophenyl                                                    
                    n-butylcarbonyl                                       
                                 OH                                       
710    4-amidinophenyl                                                    
                    propionyl    OH                                       
711    4-amidinophenyl                                                    
                    acetyl       OH                                       
712    4-amidinophenyl                                                    
                    methylsulfonyl                                        
                                 OH                                       
713    4-amidinophenyl                                                    
                    ethylsulfonyl                                         
                                 OH                                       
714    4-amidinophenyl                                                    
                    n-butylsulfonyl                                       
                                 OH                                       
715    4-amidinophenyl                                                    
                    phenylsulfonyl                                        
                                 OH                                       
716    4-amidinophenyl                                                    
                    4-methylphenyl-                                       
                                 OH                                       
                    sulfonyl                                              
717    4-amidinophenyl                                                    
                    benzylsulfonyl                                        
                                 OH   488                                 
718    4-amidinophenyl                                                    
                    2-pyridylcarbonyl                                     
                                 OH                                       
719    4-amidinophenyl                                                    
                    3-pyridylcarbonyl                                     
                                 OH                                       
720    4-amidinophenyl                                                    
                    4-pyridylcarbonyl                                     
                                 OH                                       
721    4-amidinophenyl                                                    
                    2-pyridylmethyl-                                      
                                 OH                                       
                    carbonyl                                              
722    4-amidinophenyl                                                    
                    3-pyridylmethyl-                                      
                                 OH                                       
                    carbonyl                                              
723    4-amidinophenyl                                                    
                    4-pyridylmethyl-                                      
                                 OH                                       
                    carbonyl                                              
724    4-amidinophenyl                                                    
                    2-pyridylmethoxy-                                     
                                 OH                                       
                    carbonyl                                              
725    4-amidinophenyl                                                    
                    3-pyridylmethoxy-                                     
                                 OH                                       
                    carbonyl                                              
726    4-amidinophenyl                                                    
                    4-pyridylmethoxy-                                     
                                 OH                                       
                    carbonyl                                              
727    4-amidinophenyl                                                    
                    benzyloxycarbonyl                                     
                                 OMe  480                                 
728    4-amidinophenyl                                                    
                    t-butyloxycarbonyl                                    
                                 OMe                                      
729    4-amidinophenyl                                                    
                    n-butyloxycarbonyl                                    
                                 OMe  446                                 
730    4-amidinophenyl                                                    
                    ethyloxycarbonyl                                      
                                 OMe                                      
731    4-amidinophenyl                                                    
                    methyloxycarbonyl                                     
                                 OMe                                      
732    4-amidinophenyl                                                    
                    phenylethylcarbonyl                                   
                                 OMe                                      
733    4-amidinophenyl                                                    
                    2,2-dimethyl-                                         
                                 OMe                                      
                    propylcarbonyl                                        
734    4-amidinophenyl                                                    
                    n-pentylcarbonyl                                      
                                 OMe                                      
735    4-amidinophenyl                                                    
                    n-butylcarbonyl                                       
                                 OMe                                      
736    4-amidinophenyl                                                    
                    propionyl    OMe                                      
737    4-amidinophenyl                                                    
                    acetyl       OMe                                      
738    4-amidinophenyl                                                    
                    methylsulfonyl                                        
                                 OMe                                      
739    4-amidinophenyl                                                    
                    ethylsulfonyl                                         
                                 OMe                                      
740    4-amidinophenyl                                                    
                    n-butylsulfonyl                                       
                                 OMe                                      
741    4-amidinophenyl                                                    
                    phenylsulfonyl                                        
                                 OMe                                      
742    4-amidinophenyl                                                    
                    4-methylphenyl-                                       
                                 OMe                                      
                    sulfonyl                                              
743    4-amidinophenyl                                                    
                    benzylsulfonyl                                        
                                 OMe                                      
744    4-amidinophenyl                                                    
                    2-pyridylcarbonyl                                     
                                 OMe                                      
745    4-amidinophenyl                                                    
                    3-pyridylcarbonyl                                     
                                 OMe                                      
746    4-amidinophenyl                                                    
                    4-pyridylcarbonyl                                     
                                 OMe                                      
747    4-amidinophenyl                                                    
                    2-pyridylmethyl-                                      
                                 OMe                                      
                    carbonyl                                              
748    4-amidinophenyl                                                    
                    3-pyridylmethyl-                                      
                                 OMe                                      
                    carbonyl                                              
749    4-amidinophenyl                                                    
                    4-pyridylmethyl-                                      
                                 OMe                                      
                    carbonyl                                              
750    4-amidinophenyl                                                    
                    2-pyridylmethoxy-                                     
                                 OMe                                      
                    carbonyl                                              
751    4-amidinophenyl                                                    
                    3-pyridylmethoxy-                                     
                                 OMe                                      
                    carbonyl                                              
752    4-amidinophenyl                                                    
                    4-pyridylmethoxy-                                     
                                 OMe                                      
                    carbonyl                                              
753    4-piperidinylethyl                                                 
                    benzylcarbonyl                                        
                                 OMe                                      
754    4-(BOCamidi- benzyloxycarbonyl                                     
                                 OMe                                      
       no)phenyl                                                          
755    4-(BOCamidi- n-butyloxycarbonyl                                    
                                 OMe                                      
       no)phenyl                                                          
756    4-amidinophenyl                                                    
                    1-naphthylsulfonyl                                    
                                 OMe                                      
757    4-amidinophenyl                                                    
                    2-naphthylsulfonyl                                    
                                 OMe                                      
758    4-piperidinylethyl                                                 
                    n-butyloxycarbonyl                                    
                                 OMe  440                                 
759    4-amidinophenyl                                                    
                    2-thienylsulfonyl                                     
                                 OMe                                      
760    4-amidinophenyl                                                    
                    3-methylphenyl-                                       
                                 OMe                                      
                    sulfonyl                                              
761    4-amidinophenyl                                                    
                    4-fluorophenyl-                                       
                                 OMe                                      
                    sulfonyl                                              
762    4-amidinophenyl                                                    
                    4-methoxyphenyl-                                      
                                 OMe                                      
                    sulfonyl                                              
763    4-amidinophenyl                                                    
                    n-propylsulfonyl                                      
                                 OMe                                      
764    4-amidinophenyl                                                    
                    2-phenylethyl-                                        
                                 OMe                                      
                    sulfonyl                                              
765    4-amidinophenyl                                                    
                    4-isopropylphenyl-                                    
                                 OMe                                      
                    sulfonyl                                              
766    4-amidinophenyl                                                    
                    3-phenylpropyl-                                       
                                 OMe                                      
                    sulfonyl                                              
767    4-amidinophenyl                                                    
                    3-pyridylsulfonyl                                     
                                 OMe                                      
768    4-amidinophenyl                                                    
                    2-pyridylsulfonyl                                     
                                 OMe                                      
769    4-amidinophenyl                                                    
                    n-butylamino-                                         
                                 OMe                                      
                    sulfonyl                                              
770    4-amidinophenyl                                                    
                    i-butylamino-                                         
                                 OMe                                      
                    sulfonyl                                              
771    4-amidinophenyl                                                    
                    t-butylamino-                                         
                                 OMe                                      
                    sulfonyl                                              
772    4-amidinophenyl                                                    
                    i-propylamino-                                        
                                 OMe                                      
                    sulfonyl                                              
773    4-amidinophenyl                                                    
                    cyclohexylamino-                                      
                                 OMe                                      
                    sulfonyl                                              
774    4-amidinophenyl                                                    
                    phenylamino- OMe                                      
                    sulfonyl                                              
775    4-amidinophenyl                                                    
                    benzylamino- OMe                                      
                    sulfonyl                                              
776    4-amidinophenyl                                                    
                    dimethylamino-                                        
                                 OMe                                      
                    sulfonyl                                              
777    2-fluoro-4-amidino-                                                
                    3-methylphenyl-                                       
                                 OMe                                      
       phenyl       sulfonyl                                              
778    5-amidino-2-pyridyl                                                
                    n-butyloxycarbonyl                                    
                                 OMe                                      
779    5-amidino-2-pyridyl                                                
                    3-methylphenyl-                                       
                                 OMe                                      
                    sulfonyl                                              
780    6-amidino-3-pyridyl                                                
                    n-butyloxycarbonyl                                    
                                 OMe                                      
781    6-amidino-3-pyridyl                                                
                    3-methylphenyl-                                       
                                 OMe                                      
                    sulfonyl                                              
782    4-amidinophenyl                                                    
                    phenylamino- OMe                                      
                    carbonyl                                              
783    4-amidinophenyl                                                    
                    benzylamino- OMe                                      
                    carbonyl                                              
784    4-amidinophenyl                                                    
                    n-butylamino-                                         
                                 OMe                                      
                    carbonyl                                              
785    4-amidinophenyl                                                    
                    n-hexyloxycarbonyl                                    
                                 OMe                                      
786    4-amidinophenyl                                                    
                    n-hexyloxycarbonyl                                    
                                 OH                                       
787    4-amidinophenyl                                                    
                    isobutyloxycarbonyl                                   
                                 OMe                                      
788    4-amidinophenyl                                                    
                    isobutyloxycarbonyl                                   
                                 OH                                       
789    4-amidinophenyl                                                    
                    2-cyclopropyl-                                        
                                 OMe                                      
                    ethoxycarbonyl                                        
790    4-amidinophenyl                                                    
                    2-cyclopropyl-                                        
                                 OH                                       
                    ethoxycarbonyl                                        
791    4-amidinophenyl                                                    
                    2-cyclopentyl-                                        
                                 OMe                                      
                    ethoxycarbonyl                                        
792    4-amidinophenyl                                                    
                    2-cyclopentyl-                                        
                                 OH                                       
                    ethoxycarbonyl                                        
793    4-amidinophenyl                                                    
                    n-propylsulfonyl                                      
                                 OMe                                      
794    4-amidinophenyl                                                    
                    2-methylphenyl-                                       
                                 OMe                                      
                    sulfonyl                                              
795    4-amidinophenyl                                                    
                    2-benzothienyl-                                       
                                 OMe                                      
                    sulfonyl                                              
796    4-amidinophenyl                                                    
                    2-benzothienyl-                                       
                                 OMe                                      
                    sulfonyl                                              
797    4-amidinophenyl                                                    
                    2,2,5,7,8-penta-                                      
                                 OH                                       
                    methyl                                                
                    3,4-dihydro-                                          
                    2Hbenzo-                                              
                    pyran-6-ylsulfonyl                                    
798    4-amidinophenyl                                                    
                    3-methylphenyl-                                       
                                 OH   486                                 
                    sulfonyl                                              
______________________________________                                    

              TABLE 2E                                                    
______________________________________                                    
 ##STR184##                                                               
Example                               MS                                  
Number R.sup.1 --V  R.sup.16     Y    (M +  H).sup.+                      
______________________________________                                    
801    4-amidinophenyl                                                    
                    benzyloxycarbonyl                                     
                                 OH                                       
802    4-amidinophenyl                                                    
                    t-butyloxycarbonyl                                    
                                 OH                                       
803    4-amidinophenyl                                                    
                    n-butyloxycarbonyl                                    
                                 OH                                       
804    4-amidinophenyl                                                    
                    ethyloxycarbonyl                                      
                                 OH                                       
805    4-amidinophenyl                                                    
                    methyloxycarbonyl                                     
                                 OH                                       
806    4-amidinophenyl                                                    
                    phenylethylcarbonyl                                   
                                 OH                                       
807    4-amidinophenyl                                                    
                    2,2-dimethyl-                                         
                                 OH                                       
                    propylcarbonyl                                        
808    4-amidinophenyl                                                    
                    n-pentylcarbonyl                                      
                                 OH                                       
809    4-amidinophenyl                                                    
                    n-butylcarbonyl                                       
                                 OH                                       
810    4-amidinophenyl                                                    
                    propionyl    OH                                       
811    4-amidinophenyl                                                    
                    acetyl       OH                                       
812    4-amidinophenyl                                                    
                    methylsulfonyl                                        
                                 OH                                       
813    4-amidinophenyl                                                    
                    ethylsulfonyl                                         
                                 OH                                       
814    4-amidinophenyl                                                    
                    n-butylsulfonyl                                       
                                 OH                                       
815    4-amidinophenyl                                                    
                    phenylsulfonyl                                        
                                 OH                                       
816    4-amidinophenyl                                                    
                    4-methylphenyl-                                       
                                 OH   488                                 
                    sulfonyl                                              
817    4-amidinophenyl                                                    
                    benzylsulfonyl                                        
                                 OH                                       
818    4-amidinophenyl                                                    
                    2-pyridylcarbonyl                                     
                                 OH                                       
819    4-amidinophenyl                                                    
                    3-pyridylcarbonyl                                     
                                 OH                                       
820    4-amidinophenyl                                                    
                    4-pyridylcarbonyl                                     
                                 OH                                       
821    4-amidinophenyl                                                    
                    2-pyridylmethyl-                                      
                                 OH                                       
                    carbonyl                                              
822    4-amidinophenyl                                                    
                    3-pyridylmethyl-                                      
                                 OH                                       
                    carbonyl                                              
823    4-amidinophenyl                                                    
                    4-pyridylmethyl-                                      
                                 OH                                       
                    carbonyl                                              
824    4-amidinophenyl                                                    
                    2-pyridylmethoxy-                                     
                                 OH                                       
                    carbonyl                                              
825    4-amidinophenyl                                                    
                    3-pyridylmethoxy-                                     
                                 OH                                       
                    carbonyl                                              
826    4-amidinophenyl                                                    
                    4-pyridylmethoxy-                                     
                                 OH                                       
                    carbonyl                                              
827    4-amidinophenyl                                                    
                    benzyloxycarbonyl                                     
                                 OMe                                      
828    4-amidinophenyl                                                    
                    t-butyloxycarbonyl                                    
                                 OMe                                      
829    4-amidinophenyl                                                    
                    n-butyloxycarbonyl                                    
                                 OMe  448                                 
830    4-amidinophenyl                                                    
                    ethyloxycarbonyl                                      
                                 OMe                                      
831    4-amidinophenyl                                                    
                    methyloxycarbonyl                                     
                                 OMe                                      
832    4-amidinophenyl                                                    
                    phenylethylcarbonyl                                   
                                 OMe                                      
833    4-amidinophenyl                                                    
                    2,2-dimethyl-                                         
                                 OMe                                      
                    propylcarbonyl                                        
834    4-amidinophenyl                                                    
                    n-pentylcarbonyl                                      
                                 OMe                                      
835    4-amidinophenyl                                                    
                    n-butylcarbonyl                                       
                                 OMe                                      
836    4-amidinophenyl                                                    
                    propionyl    OMe                                      
837    4-amidinophenyl                                                    
                    acetyl       OMe                                      
838    4-amidinophenyl                                                    
                    methylsulfonyl                                        
                                 OMe                                      
839    4-amidinophenyl                                                    
                    ethylsulfonyl                                         
                                 OMe                                      
840    4-amidinophenyl                                                    
                    n-butylsulfonyl                                       
                                 OMe                                      
841    4-amidinophenyl                                                    
                    phenylsulfonyl                                        
                                 OMe                                      
842    4-amidinophenyl                                                    
                    4-methylphenyl-                                       
                                 OMe                                      
                    sulfonyl                                              
843    4-amidinophenyl                                                    
                    benzylsulfonyl                                        
                                 OMe                                      
844    4-amidinophenyl                                                    
                    2-pyridylcarbonyl                                     
                                 OMe                                      
845    4-amidinophenyl                                                    
                    3-pyridylcarbonyl                                     
                                 OMe                                      
846    4-amidinophenyl                                                    
                    4-pyridylcarbonyl                                     
                                 OMe                                      
847    4-amidinophenyl                                                    
                    2-pyridylmethyl-                                      
                                 OMe                                      
                    carbonyl                                              
848    4-amidinophenyl                                                    
                    3-pyridylmethyl-                                      
                                 OMe                                      
                    carbonyl                                              
849    4-amidinophenyl                                                    
                    4-pyridylmethyl-                                      
                                 OMe                                      
                    carbonyl                                              
850    4-amidinophenyl                                                    
                    2-pyridylmethoxy-                                     
                                 OMe                                      
                    carbonyl                                              
851    4-amidinophenyl                                                    
                    3-pyridylmethoxy-                                     
                                 OMe                                      
                    carbonyl                                              
852    4-amidinophenyl                                                    
                    4-pyridylmethoxy-                                     
                                 OMe                                      
                    carbonyl                                              
853    4-piperidinylethyl                                                 
                    benzylcarbonyl                                        
                                 OMe                                      
854    4-(BOCamidi- benzyloxycarbonyl                                     
                                 OMe                                      
       no)phenyl                                                          
855    4-(BOCamidi- n-butyloxycarbonyl                                    
                                 OMe                                      
       no)phenyl                                                          
856    4-amidinophenyl                                                    
                    1-naphthylsulfonyl                                    
                                 OMe                                      
857    4-amidinophenyl                                                    
                    2-naphthylsulfonyl                                    
                                 OMe                                      
858    4-piperidinylethyl                                                 
                    n-butyloxycarbonyl                                    
                                 OMe                                      
859    4-amidinophenyl                                                    
                    2-thienylsulfonyl                                     
                                 OMe                                      
860    4-amidinophenyl                                                    
                    3-methylphenyl-                                       
                                 OMe                                      
                    sulfonyl                                              
861    4-amidinophenyl                                                    
                    4-fluorophenyl-                                       
                                 OMe                                      
                    sulfonyl                                              
862    4-amidinophenyl                                                    
                    4-methoxyphenyl-                                      
                                 OMe                                      
                    sulfonyl                                              
863    4-amidinophenyl                                                    
                    n-propylsulfonyl                                      
                                 OMe                                      
864    4-amidinophenyl                                                    
                    2-phenylethyl-                                        
                                 OMe                                      
                    sulfonyl                                              
865    4-amidinophenyl                                                    
                    4-isopropylphenyl-                                    
                                 OMe                                      
                    sulfonyl                                              
866    4-amidinophenyl                                                    
                    3-phenylpropyl-                                       
                                 OMe                                      
                    sulfonyl                                              
867    4-amidinophenyl                                                    
                    3-pyridylsulfonyl                                     
                                 OMe                                      
868    4-amidinophenyl                                                    
                    2-pyridylsulfonyl                                     
                                 OMe                                      
869    4-amidinophenyl                                                    
                    n-butylamino-                                         
                                 OMe                                      
                    sulfonyl                                              
870    4-amidinophenyl                                                    
                    i-butylamino-                                         
                                 OMe                                      
                    sulfonyl                                              
871    4-amidinophenyl                                                    
                    t-butylamino-                                         
                                 OMe                                      
                    sulfonyl                                              
872    4-amidinophenyl                                                    
                    i-propylamino-                                        
                                 OMe                                      
                    sulfonyl                                              
873    4-amidinophenyl                                                    
                    cyclohexylamino-                                      
                                 OMe                                      
                    sulfonyl                                              
874    4-amidinophenyl                                                    
                    phenylamino- OMe                                      
                    sulfonyl                                              
875    4-amidinophenyl                                                    
                    benzylamino- OMe                                      
                    sulfonyl                                              
876    4-amidinophenyl                                                    
                    dimethylamino-                                        
                                 OMe                                      
                    sulfonyl                                              
877    2-fluoro-4-amidino-                                                
                    3-methylphenyl-                                       
                                 OMe                                      
       phenyl       sulfonyl                                              
878    5-amidino-2-pyridyl                                                
                    n-butyloxycarbonyl                                    
                                 OMe                                      
879    5-amidino-2-pyridyl                                                
                    3-methylphenyl-                                       
                                 OMe                                      
                    sulfonyl                                              
880    6-amidino-3-pyridyl                                                
                    n-butyloxycarbonyl                                    
                                 OMe                                      
881    6-amidino-3-pyridyl                                                
                    3-methylphenyl-                                       
                                 OMe                                      
                    sulfonyl                                              
882    4-amidinophenyl                                                    
                    phenylamino- OMe                                      
                    carbonyl                                              
883    4-amidinophenyl                                                    
                    benzylamino- OMe                                      
                    carbonyl                                              
884    4-amidinophenyl                                                    
                    n-butylamino-                                         
                                 OMe                                      
                    carbonyl                                              
885    4-amidinophenyl                                                    
                    n-hexyloxycarbonyl                                    
                                 OMe                                      
886    4-amidinophenyl                                                    
                    n-hexyloxycarbonyl                                    
                                 OH                                       
887    4-amidinophenyl                                                    
                    isobutyloxycarbonyl                                   
                                 OMe                                      
888    4-amidinophenyl                                                    
                    isobutyloxycarbonyl                                   
                                 OH                                       
889    4-amidinophenyl                                                    
                    2-cyclopropyl-                                        
                                 OMe                                      
                    ethoxycarbonyl                                        
890    4-amidinophenyl                                                    
                    2-cyclopropyl-                                        
                                 OH                                       
                    ethoxycarbonyl                                        
891    4-amidinophenyl                                                    
                    2-cyclopentyl-                                        
                                 OMe                                      
                    ethoxycarbonyl                                        
892    4-amidinophenyl                                                    
                    2-cyclopentyl-                                        
                                 OH                                       
                    ethoxycarbonyl                                        
893    4-amidinophenyl                                                    
                    n-propylsulfonyl                                      
                                 OMe                                      
894    4-amidinophenyl                                                    
                    2-methylphenyl                                        
                                 OMe                                      
                    sulfonyl                                              
895    4-amidinophenyl                                                    
                    2-benzothienyl-                                       
                                 OMe                                      
                    sulfonyl                                              
896    4-amidinophenyl                                                    
                    2-benzothienyl                                        
                                 OMe                                      
                    sulfonyl                                              
897    4-amidinophenyl                                                    
                    2,2,5,7,8-penta-                                      
                                 OH                                       
                    methyl                                                
                    3,4-dihydro-                                          
                    2Hbenzo-                                              
                    pyran-6-ylsulfonyl                                    
______________________________________                                    

                                  TABLE 3                                 
__________________________________________________________________________
                                                   (VII)                  
 ##STR185##                                                               
Ex.                                              MS                       
No.                                                                       
   R.sup.2                                                                
      R.sup.1 --V    --F--E<                                              
                            p n'                                          
                                Y                (M +  H).sup.+           
__________________________________________________________________________
171                                                                       
   H                                                                      
       ##STR186##    --C(═O)--N<                                      
                            1 1 OH                                        
172                                                                       
   H                                                                      
       ##STR187##    --C(═O)--N<                                      
                            1 2 OH                                        
173                                                                       
   H                                                                      
       ##STR188##    --C(H.sub.2)--N<                                     
                            1 1 OH                                        
174                                                                       
   H                                                                      
       ##STR189##    --C(H.sub.2)--N<                                     
                            1 2 OH                                        
175                                                                       
   H                                                                      
       ##STR190##    --C(H)═C<                                        
                            1 1 OH                                        
176                                                                       
   H                                                                      
       ##STR191##    --C(H)═C<                                        
                            1 2 OH                                        
177                                                                       
   H                                                                      
       ##STR192##    --C(═O)--N<                                      
                            2 1 OH                                        
178                                                                       
   H                                                                      
       ##STR193##    --C(═O)--N<                                      
                            2 2 OH                                        
179                                                                       
   H                                                                      
       ##STR194##    --C(H.sub.2)--N<                                     
                            2 1 OH                                        
180                                                                       
   H                                                                      
       ##STR195##    --C(H.sub.2)--N<                                     
                            2 2 OH                                        
181                                                                       
   H                                                                      
       ##STR196##    --C(H)═C<                                        
                            2 1 OH                                        
182                                                                       
   H                                                                      
       ##STR197##    --C(H)═C<                                        
                            2 2 OH                                        
183                                                                       
   H                                                                      
       ##STR198##    --C(═O)--N<                                      
                            3 1 OH                                        
184                                                                       
   H                                                                      
       ##STR199##    --C(═O)--N<                                      
                            3 2 OH                                        
185                                                                       
   H                                                                      
       ##STR200##    --C(H.sub.2)--N<                                     
                            3 1 OH                                        
186                                                                       
   H                                                                      
       ##STR201##    --C(H.sub.2)--N<                                     
                            3 2 OH                                        
187                                                                       
   H                                                                      
       ##STR202##    --C(H)═C<                                        
                            3 1 OH                                        
188                                                                       
   H                                                                      
       ##STR203##    --C(H)═C<                                        
                            3 2 OH                                        
189                                                                       
   H                                                                      
       ##STR204##    --C(═O)--N<                                      
                            1 1 OH               338                      
190                                                                       
   H                                                                      
       ##STR205##    --C(═O)--N<                                      
                            1 2 OH               352                      
191                                                                       
   H                                                                      
       ##STR206##    --C(H.sub.2)--N<                                     
                            1 1 OH                                        
192                                                                       
   H                                                                      
       ##STR207##    --C(H.sub.2)--N<                                     
                            1 2 OH                                        
193                                                                       
   H                                                                      
       ##STR208##    --C(H)═C<                                        
                            1 1 OH                                        
194                                                                       
   H                                                                      
       ##STR209##    --C(H)═C<                                        
                            1 2 OH                                        
195                                                                       
   H                                                                      
       ##STR210##    --C(═O)--N<                                      
                            2 1 OH                                        
196                                                                       
   H                                                                      
       ##STR211##    --C(═O)--N<                                      
                            2 2 OH                                        
197                                                                       
   H                                                                      
       ##STR212##    --C(H.sub.2)--N<                                     
                            2 1 OH                                        
198                                                                       
   H                                                                      
       ##STR213##    --C(H.sub.2)--N<                                     
                            2 2 OH                                        
199                                                                       
   H                                                                      
       ##STR214##    --C(H)═C<                                        
                            2 1 OH                                        
200                                                                       
   H                                                                      
       ##STR215##    --C(H)═C<                                        
                            2 2 OH                                        
201                                                                       
   H                                                                      
       ##STR216##    --C(═O)--N<                                      
                            3 1 OH                                        
202                                                                       
   H                                                                      
       ##STR217##    --C(═O)--N<                                      
                            3 2 OH                                        
203                                                                       
   H                                                                      
       ##STR218##    --C(H.sub.2)--N<                                     
                            3 1 OH                                        
204                                                                       
   H                                                                      
       ##STR219##    --C(H.sub.2)--N<                                     
                            3 2 OH                                        
205                                                                       
   H                                                                      
       ##STR220##    --C(H)═C<                                        
                            3 1 OH                                        
206                                                                       
   H                                                                      
       ##STR221##    --C(H)═C<                                        
                            3 2 OH                                        
207                                                                       
   Boc                                                                    
       ##STR222##    --C(═O)--N<                                      
                            1 1 OH                                        
208                                                                       
   Cbz                                                                    
       ##STR223##    --C(═O)--N<                                      
                            1 1 OH                                        
209                                                                       
   H                                                                      
       ##STR224##    --C(═O)--N<                                      
                            1 1                                           
                                 ##STR225##                               
210                                                                       
   H                                                                      
       ##STR226##    --C(═O)--N<                                      
                            1 1                                           
                                 ##STR227##                               
211                                                                       
   H                                                                      
       ##STR228##    --C(═O)--N<                                      
                            1 1                                           
                                 ##STR229##                               
212                                                                       
   H                                                                      
       ##STR230##    --C(═O)--N<                                      
                            1 1                                           
                                 ##STR231##                               
213                                                                       
   H                                                                      
       ##STR232##    --C(═O)--N<                                      
                            1 1                                           
                                 ##STR233##                               
214                                                                       
   H                                                                      
       ##STR234##    --C(═O)--N<                                      
                            1 1 OEt                                       
215                                                                       
   H                                                                      
       ##STR235##    --C(═O)--N<                                      
                            1 2 OEt                                       
216                                                                       
   H                                                                      
       ##STR236##    --C(H.sub.2)--N<                                     
                            1 1 OEt                                       
217                                                                       
   H                                                                      
       ##STR237##    --C(H.sub.2)--N<                                     
                            1 2 OEt                                       
218                                                                       
   H                                                                      
       ##STR238##    --C(H)═C<                                        
                            1 1 OEt                                       
219                                                                       
   H                                                                      
       ##STR239##    --C(H)═C<                                        
                            1 2 OEt                                       
220                                                                       
   H                                                                      
       ##STR240##    --C(═O)--N<                                      
                            2 1 OEt                                       
221                                                                       
   H                                                                      
       ##STR241##    --C(═O)--N<                                      
                            2 2 OEt                                       
222                                                                       
   H                                                                      
       ##STR242##    --C(H.sub.2)--N<                                     
                            2 1 OEt                                       
223                                                                       
   H                                                                      
       ##STR243##    --C(H.sub.2)--N<                                     
                            2 2 OEt                                       
224                                                                       
   H                                                                      
       ##STR244##    --C(H)═C<                                        
                            2 1 OEt                                       
225                                                                       
   H                                                                      
       ##STR245##    --C(H)═C<                                        
                            2 2 OEt                                       
226                                                                       
   H                                                                      
       ##STR246##    --C(═O)--N<                                      
                            3 1 OEt                                       
227                                                                       
   H                                                                      
       ##STR247##    --C(═O)--N<                                      
                            3 2 OEt                                       
228                                                                       
   H                                                                      
       ##STR248##    --C(H.sub.2)--N<                                     
                            3 1 OEt                                       
229                                                                       
   H                                                                      
       ##STR249##    --C(H.sub.2)--N<                                     
                            3 2 OEt                                       
230                                                                       
   H                                                                      
       ##STR250##    --C(H)═C<                                        
                            3 1 OEt                                       
231                                                                       
   H                                                                      
       ##STR251##    --C(H)═C<                                        
                            3 2 OEt                                       
232                                                                       
   H                                                                      
       ##STR252##    --C(═O)--N<                                      
                            1 1 OEt                                       
233                                                                       
   H                                                                      
       ##STR253##    --C(═O)--N<                                      
                            1 2 OEt                                       
234                                                                       
   H                                                                      
       ##STR254##    --C(H.sub.2)--N<                                     
                            1 1 OEt                                       
235                                                                       
   H                                                                      
       ##STR255##    --C(H.sub.2)--N<                                     
                            1 2 OEt                                       
236                                                                       
   H                                                                      
       ##STR256##    --C(H)═C<                                        
                            1 1 OEt                                       
237                                                                       
   H                                                                      
       ##STR257##    --C(H)═C<                                        
                            1 2 OEt                                       
238                                                                       
   H                                                                      
       ##STR258##    --C(═O)--N<                                      
                            2 1 OEt                                       
239                                                                       
   H                                                                      
       ##STR259##    --C(═O)--N<                                      
                            2 2 OEt                                       
240                                                                       
   H                                                                      
       ##STR260##    --C(H.sub.2)--N<                                     
                            2 1 OEt                                       
241                                                                       
   H                                                                      
       ##STR261##    --C(H.sub.2)--N<                                     
                            2 2 OEt                                       
242                                                                       
   H                                                                      
       ##STR262##    --C(H)═C<                                        
                            2 1 OEt                                       
243                                                                       
   H                                                                      
       ##STR263##    --C(H)═C<                                        
                            2 2 OEt                                       
244                                                                       
   H                                                                      
       ##STR264##    --C(═O)--N<                                      
                            3 1 OEt                                       
245                                                                       
   H                                                                      
       ##STR265##    --C(═O)--N<                                      
                            3 2 OEt                                       
246                                                                       
   H                                                                      
       ##STR266##    --C(H.sub.2)--N<                                     
                            3 1 OEt                                       
247                                                                       
   H                                                                      
       ##STR267##    --C(H.sub.2)--N<                                     
                            3 2 OEt                                       
248                                                                       
   H                                                                      
       ##STR268##    --C(H)═C<                                        
                            3 1 OEt                                       
249                                                                       
   H                                                                      
       ##STR269##    --C(H)═C<                                        
                            3 2 OEt                                       
250                                                                       
   Boc                                                                    
       ##STR270##    --C(═O)--N<                                      
                            1 1 OEt                                       
251                                                                       
   Cbz                                                                    
       ##STR271##    --C(═O)--N<                                      
                            1 1 OEt                                       
373                                                                       
   H                                                                      
       ##STR272##    --C(═O)--N<                                      
                            1 2 OH               366                      
__________________________________________________________________________

                                  TABLE 4                                 
__________________________________________________________________________
                                    (VIII)                                
 ##STR273##                                                               
Example                                                                   
Number                                                                    
     R.sup.2                                                              
        R.sup.1a    Z.sup.1                                               
                        Y                                                 
__________________________________________________________________________
252  H                                                                    
         ##STR274## CH.sub.2                                              
                        OH                                                
253  H  --NHCH.sub.2).sub.2 --                                            
                    CH.sub.2                                              
                        OH                                                
254  H  --NHCH.sub.2).sub.3 --                                            
                    CH.sub.2                                              
                        OH                                                
255  H                                                                    
         ##STR275## O   OH                                                
256  H  --NHCH.sub.2).sub.2 --                                            
                    O   OH                                                
257  H  --NHCH.sub.2).sub.3 --                                            
                    O   OH                                                
258  Boc                                                                  
         ##STR276## CH.sub.2                                              
                        OH                                                
259  Cbz                                                                  
         ##STR277## CH.sub.2                                              
                        OH                                                
260  H                                                                    
         ##STR278## CH.sub.2                                              
                         ##STR279##                                       
261  H                                                                    
         ##STR280## CH.sub.2                                              
                         ##STR281##                                       
262  H                                                                    
         ##STR282## CH.sub.2                                              
                         ##STR283##                                       
263  H                                                                    
         ##STR284## CH.sub.2                                              
                         ##STR285##                                       
264  H                                                                    
         ##STR286## CH.sub.2                                              
                         ##STR287##                                       
265  H                                                                    
         ##STR288## CH.sub.2                                              
                        OEt                                               
266  H                                                                    
         ##STR289## CH.sub.2                                              
                        OEt                                               
267  H                                                                    
         ##STR290## CH.sub.2                                              
                        OEt                                               
268  H  --NH(CH.sub.2).sub.2 --                                           
                    CH.sub.2                                              
                        OEt                                               
269  H  --NH(CH.sub.2).sub.3 --                                           
                    CH.sub.2                                              
                        OEt                                               
270  H                                                                    
         ##STR291## O   OEt                                               
271  H  --NH(CH.sub.2).sub.2 --                                           
                    O   OEt                                               
272  H  --NH(CH.sub.2).sub.3 --                                           
                    O   OEt                                               
273  Boc                                                                  
         ##STR292## CH.sub.2                                              
                        OEt                                               
274  Cbz                                                                  
         ##STR293## CH.sub.2                                              
                        OEt                                               
__________________________________________________________________________

              TABLE 5                                                     
______________________________________                                    
 ##STR294##                                                               
Example                             MS (ESI)                              
Number R                     Y      (M +  H).sup.+                        
______________________________________                                    
375                                                                       
        ##STR295##           OH     373                                   
376                                                                       
        ##STR296##           OH                                           
377                                                                       
        ##STR297##           OH     387                                   
378                                                                       
        ##STR298##           OH                                           
379                                                                       
        ##STR299##           OH                                           
380                                                                       
        ##STR300##           OH                                           
381                                                                       
        ##STR301##           OH                                           
382                                                                       
        ##STR302##           OH                                           
383                                                                       
        ##STR303##           OH     415                                   
384                                                                       
        ##STR304##           OH                                           
385                                                                       
        ##STR305##           OH                                           
386                                                                       
        ##STR306##           OH                                           
387                                                                       
        ##STR307##           OH                                           
388                                                                       
        ##STR308##           OH                                           
389                                                                       
        ##STR309##           OH                                           
394                                                                       
        ##STR310##           OMe    387                                   
395                                                                       
        ##STR311##           OMe                                          
396                                                                       
        ##STR312##           OMe                                          
397                                                                       
        ##STR313##           OMe                                          
398                                                                       
        ##STR314##           OMe                                          
399                                                                       
        ##STR315##           OMe                                          
400                                                                       
        ##STR316##           OMe    402                                   
401                                                                       
        ##STR317##           OMe                                          
402                                                                       
        ##STR318##           OMe                                          
403                                                                       
        ##STR319##           OMe                                          
404                                                                       
        ##STR320##           OMe                                          
405                                                                       
        ##STR321##           OMe                                          
406                                                                       
        ##STR322##           OMe                                          
407                                                                       
        ##STR323##           OMe                                          
408                                                                       
        ##STR324##           OMe                                          
413                                                                       
        ##STR325##           OEt    401                                   
414                                                                       
        ##STR326##           OEt                                          
415                                                                       
        ##STR327##           OEt    415                                   
416                                                                       
        ##STR328##           OEt                                          
417                                                                       
        ##STR329##           OEt                                          
418                                                                       
        ##STR330##           OEt                                          
419                                                                       
        ##STR331##           OEt                                          
420                                                                       
        ##STR332##           OEt                                          
421                                                                       
        ##STR333##           OEt                                          
422                                                                       
        ##STR334##           OEt                                          
423                                                                       
        ##STR335##           OEt                                          
424                                                                       
        ##STR336##           OEt                                          
425                                                                       
        ##STR337##           OEt                                          
426                                                                       
        ##STR338##           OEt                                          
427                                                                       
        ##STR339##           OEt                                          
432    --NHC(CH.sub.3).sub.2 --                                           
                             OEt.                                         
       CH.sub.2 C(═O)Y                                                
433    --N(CH.sub.2 C.sub.6 H.sub.5)--                                    
                             OEt                                          
       (CH.sub.2).sub.2 C(═O)Y                                        
436                                                                       
        ##STR340##           OEt    387                                   
437                                                                       
        ##STR341##           OEt    387                                   
438                                                                       
        ##STR342##           OMe    387                                   
899                                                                       
        ##STR343##           OMe                                          
900                                                                       
        ##STR344##           OH                                           
______________________________________                                    

                                  TABLE 6                                 
__________________________________________________________________________
 ##STR345##                                                               
Ex.                                    (M +  H).sup.+                     
No.                                                                       
   R.sup.2                                                                
         R.sup.3                                                          
             R.sup.4a       X     Y    ESI                                
__________________________________________________________________________
950                                                                       
   H     H   3-methyl-      2-fluoro-                                     
                                  OCH.sub.3                               
                                       521                                
             phenyl-        phen-1,4-                                     
             sulfonyl       diyl                                          
951                                                                       
   H     H   3-methyl-      2-fluoro-                                     
                                  OH   507                                
             phenyl-        phen-1,4-                                     
             sulfonyl       diyl                                          
952                                                                       
    ##STR346##                                                            
         H   3-methyl-  phenyl-  sulfonyl                                 
phen-1,4-  diyl                                                           
   OCH.sub.3                                                              
         545                                                              
953                                                                       
    ##STR347##                                                            
         H   3-methyl-  phenyl-  sulfonyl                                 
phen-1,4-  diyl                                                           
   OH    532                                                              
954                                                                       
   H     H   n-butoxy-                                                    
phen-1,4-                                                                 
   OH    435                                                              
             carbonyl       diyl                                          
955                                                                       
   H     H   3-methyl-                                                    
phen-1,4-                                                                 
   OCH.sub.3                                                              
         503                                                              
             phenyl-        diyl                                          
             sulfonyl                                                     
956                                                                       
   H     H   3-methyl-                                                    
phen-1,4-                                                                 
   OH    489                                                              
             phenyl-        diyl                                          
             sulfonyl                                                     
957                                                                       
   H     H                                                                
              ##STR348##                                                  
phen-1,4-  diyl                                                           
   OH    527                                                              
958                                                                       
   H     H   4-CF.sub.3 -                                                 
phen-1,4-                                                                 
   OH    543                                                              
             phenyl-        diyl                                          
             sulfonyl                                                     
959                                                                       
   H     H                                                                
              ##STR349##                                                  
phen-1,4-  diyl                                                           
   OH                                                                     
960                                                                       
   o-CH.sub.3 O-                                                          
         H   3-methyl-                                                    
phen-1,4-                                                                 
   OH                                                                     
   benzyl    phenyl-        diyl                                          
             sulfonyl                                                     
961                                                                       
   o-CH.sub.3 O-  benzyl                                                  
         H                                                                
              ##STR350##                                                  
phen-1,4-  diyl                                                           
   OH                                                                     
962                                                                       
   o-CH.sub.3 O-  benzyl                                                  
         CH.sub.3                                                         
              ##STR351##                                                  
phen-1,4-  diyl                                                           
   OH                                                                     
963                                                                       
   o-CH.sub.3 O-                                                          
         CH.sub.3                                                         
             3-methyl-                                                    
phen-1,4-                                                                 
   OH                                                                     
   benzyl    phenyl-        diyl                                          
             sulfonyl                                                     
964                                                                       
   H     H   2-fluoro-                                                    
phen-1,4-                                                                 
   OH    493                                                              
             phenyl-        diyl                                          
             sulfonyl                                                     
965                                                                       
   H     H   4-CF.sub.3 -                                                 
phen-1,4-                                                                 
   OH    543                                                              
             phenyl-        diyl                                          
             sulfonyl                                                     
966                                                                       
   H     H   4-Cl-                                                        
phen-1,4-                                                                 
   OH    509                                                              
             phenyl-        diyl                                          
             sulfonyl                                                     
967                                                                       
   H     H                                                                
              ##STR352##                                                  
phen-1,4-  diyl                                                           
   OH    525                                                              
968                                                                       
   3-(CF.sub.3)-  benzyl                                                  
         H                                                                
              ##STR353##                                                  
phen-1,4-  diyl                                                           
   OH                                                                     
969                                                                       
   3-(CF.sub.3)-  benzyl                                                  
         H                                                                
              ##STR354##                                                  
phen-1,4-  diyl                                                           
   OH                                                                     
970                                                                       
   3-(CF.sub.3)-                                                          
         CH.sub.3                                                         
             3-methyl                                                     
phen-1,4-                                                                 
   OH                                                                     
   benzyl    phenyl-        diyl                                          
             sulfonyl                                                     
971                                                                       
   3-(CF.sub.3)-  benzyl                                                  
         CH.sub.3                                                         
              ##STR355##                                                  
phen-1,4-  diyl                                                           
   OH                                                                     
972                                                                       
   nBu-  H   3-methyl-                                                    
phen-1,4-                                                                 
   OH                                                                     
             phenyl-        diyl                                          
             sulfonyl                                                     
973                                                                       
   nBu-  H                                                                
              ##STR356##                                                  
phen-1,4-  diyl                                                           
   OH                                                                     
974                                                                       
   nBu-  CH.sub.3                                                         
             3-methyl-                                                    
phen-1,4-                                                                 
   OH                                                                     
             phenyl-        diyl                                          
             sulfonyl                                                     
975                                                                       
   nBu-  CH.sub.3                                                         
              ##STR357##                                                  
phen-1,4-  diyl                                                           
   OH                                                                     
976                                                                       
   CH.sub.3                                                               
         CH.sub.3                                                         
              ##STR358##                                                  
phen-1,4-  diyl                                                           
   OH                                                                     
977                                                                       
   CH.sub.3                                                               
         CH.sub.3                                                         
             3-methyl                                                     
phen-1,4-                                                                 
   OH                                                                     
             phenyl-        diyl                                          
             sulfonyl                                                     
978                                                                       
   H     H   3-methyl-      5-    OMe  490                                
             phenyl-        carboxamido                                   
             sulfonyl       pyrid-2-yl                                    
979                                                                       
   H     H   4-ethyl-                                                     
phen-1,4-                                                                 
   OH    503                                                              
             phenyl-        diyl                                          
             sulfonyl                                                     
__________________________________________________________________________

              TABLE 7                                                     
______________________________________                                    
 ##STR359##                                                               
                                        MS                                
Ex                                      (M +                              
No.   R.sup.1 -V     R.sup.16      Y    H).sup.+                          
______________________________________                                    
980   4-amidinophenyl                                                     
                     H             OH                                     
981   4-amidinophenyl                                                     
                     benzyloxycarbonyl                                    
                                   OH                                     
982   4-amidinophenyl                                                     
                     t-butyloxycarbonyl                                   
                                   OH                                     
983   4-amidinophenyl                                                     
                     n-butyloxycarbonyl                                   
                                   OH                                     
984   4-amidinophenyl                                                     
                     ethyloxycarbonyl                                     
                                   OH                                     
985   4-amidinophenyl                                                     
                     methyloxycarbonyl                                    
                                   OH                                     
986   4-amidinophenyl                                                     
                     phenylethylcarbonyl                                  
                                   OH                                     
987   4-amidinophenyl                                                     
                     2,2-dimethyl- OH                                     
                     propylcarbonyl                                       
988   4-amidinophenyl                                                     
                     n-pentylcarbonyl                                     
                                   OH                                     
989   4-amidinophenyl                                                     
                     n-butylcarbonyl                                      
                                   OH                                     
990   4-amidinophenyl                                                     
                     propionyl     OH                                     
991   4-amidinophenyl                                                     
                     acetyl        OH                                     
992   4-amidinophenyl                                                     
                     methylsulfonyl                                       
                                   OH                                     
993   4-amidinophenyl                                                     
                     ethylsulfonyl OH                                     
994   4-amidinophenyl                                                     
                     n-butylsulfonyl                                      
                                   OH                                     
995   4-amidinophenyl                                                     
                     phenylsulfonyl                                       
                                   OH                                     
996   4-amidinophenyl                                                     
                     4-methylphenyl-                                      
                                   OH   474                               
                     sulfonyl                                             
997   4-amidinophenyl                                                     
                     benzylsulfonyl                                       
                                   OH                                     
998   4-amidinophenyl                                                     
                     2-pyridylcarbonyl                                    
                                   OH                                     
999   4-amidinophenyl                                                     
                     3-pyridylcarbonyl                                    
                                   OH                                     
1000  4-amidinophenyl                                                     
                     4-pyridylcarbonyl                                    
                                   OH                                     
1001  4-amidinophenyl                                                     
                     2-pyridylmethyl-                                     
                                   OH                                     
                     carbonyl                                             
1002  4-amidinophenyl                                                     
                     3-pyridylmethyl-                                     
                                   OH                                     
                     carbonyl                                             
1003  4-amidinophenyl                                                     
                     4-pyridylmethyl-                                     
                                   OH                                     
                     carbonyl                                             
1004  4-amidinophenyl                                                     
                     2-pyridylmethoxy-                                    
                                   OH                                     
                     carbonyl                                             
1005  4-amidinophenyl                                                     
                     3-pyridylmethoxy-                                    
                                   OH                                     
                     carbonyl                                             
1006  4-amidinophenyl                                                     
                     4-pyridylmethoxy-                                    
                                   OH                                     
                     carbonyl                                             
1007  4-amidinophenyl                                                     
                     H             OMe                                    
1008  4-amidinophenyl                                                     
                     benzyloxycarbonyl                                    
                                   OMe                                    
1009  4-amidinophenyl                                                     
                     t-butyloxycarbonyl                                   
                                   OMe                                    
1010  4-amidinophenyl                                                     
                     n-butyloxycarbonyl                                   
                                   OMe                                    
1011  4-amidinophenyl                                                     
                     ethyloxycarbonyl                                     
                                   OMe                                    
1012  4-amidinophenyl                                                     
                     methyloxycarbonyl                                    
                                   OMe                                    
1013  4-amidinophenyl                                                     
                     phenylethylcarbonyl                                  
                                   OMe                                    
1014  4-amidinophenyl                                                     
                     2,2-dimethyl- OMe                                    
                     propylcarbonyl                                       
1015  4-amidinophenyl                                                     
                     n-pentylcarbonyl                                     
                                   OMe                                    
1016  4-amidinophenyl                                                     
                     n-butylcarbonyl                                      
                                   OMe                                    
1017  4-amidinophenyl                                                     
                     propionyl     OMe                                    
1018  4-amidinophenyl                                                     
                     acetyl        OMe                                    
1019  4-amidinophenyl                                                     
                     methylsulfonyl                                       
                                   OMe                                    
1020  4-amidinophenyl                                                     
                     ethylsulfonyl OMe                                    
1021  4-amidinophenyl                                                     
                     n-butylsulfonyl                                      
                                   OMe                                    
1022  4-amidinophenyl                                                     
                     phenylsulfonyl                                       
                                   OMe                                    
1023  4-amidinophenyl                                                     
                     4-methylphenyl-                                      
                                   OMe                                    
                     sulfonyl                                             
1024  4-amidinophenyl                                                     
                     benzylfulfonyl                                       
                                   OMe                                    
1025  4-amidinophenyl                                                     
                     2-pyridylcarbonyl                                    
                                   OMe                                    
1026  4-amidinophenyl                                                     
                     3-pyridylcarbonyl                                    
                                   OMe                                    
1027  4-amidinophenyl                                                     
                     4-pyridylcarbonyl                                    
                                   OMe                                    
1029  4-amidinophenyl                                                     
                     2-pyridylmethyl-                                     
                                   OMe                                    
                     carbonyl                                             
1030  4-amidinophenyl                                                     
                     3-pyridylmethyl-                                     
                                   OMe                                    
                     carbonyl                                             
1031  4-amidinophenyl                                                     
                     4-pyridylmethyl-                                     
                                   OMe                                    
                     carbonyl                                             
1032  4-amidinophenyl                                                     
                     2-pyridylmethoxy-                                    
                                   OMe                                    
                     carbonyl                                             
1033  4-amidinophenyl                                                     
                     3-pyridylmethoxy-                                    
                                   OMe                                    
                     carbonyl                                             
1034  4-amidinophenyl                                                     
                     4-pyridylmethoxy-                                    
                                   OMe                                    
                     carbonyl                                             
1035  4-piperidinylethyl                                                  
                     benzylcarbonyl                                       
                                   OMe                                    
1036  4-(BOCamidino)phenyl                                                
                     benzyloxycarbonyl                                    
                                   OMe                                    
1037  4-(BOCamidino)phenyl                                                
                     n-butyloxycarbonyl                                   
                                   OMe                                    
1038  4-amidinophenyl                                                     
                     1-naphthylsulfonyl                                   
                                   OMe                                    
1039  4-amidinophenyl                                                     
                     2-naphthylsulfonyl                                   
                                   OMe                                    
1040  4-amidinophenyl                                                     
                     styrylsulfonyl                                       
                                   OMe                                    
1041  4-piperidinylethyl                                                  
                     n-butyloxycarbonyl                                   
                                   OMe                                    
1042  4-amidinophenyl                                                     
                     4-butyloxyphenyl-                                    
                                   OMe                                    
                     sulfonyl                                             
1043  4-amidinophenyl                                                     
                     2-thienylsulfonyl                                    
                                   OMe                                    
1044  4-amidinophenyl                                                     
                     3-methylphenyl-                                      
                                   OMe                                    
                     sulfonyl                                             
1045  4-amidinophenyl                                                     
                     4-iodophenyl  OMe                                    
1046  4-amidinophenyl                                                     
                     3-trifluoromethyl-                                   
                                   OMe                                    
                     phenylsulfonyl                                       
1047  4-amidinophenyl                                                     
                     3-chlorophenyl-                                      
                                   OMe                                    
                     sulfonyl                                             
1048  4-amidinophenyl                                                     
                     2-methoxycarbonyl-                                   
                                   OMe                                    
                     phenylsulfonyl                                       
1050  4-amidinophenyl                                                     
                     2,4,6-trimethyl-                                     
                                   OMe                                    
                     phenylsulfonyl                                       
1051  4-amidinophenyl                                                     
                     2-chlorophenyl-                                      
                                   OMe                                    
                     sulfonyl                                             
1052  4-amidinophenyl                                                     
                     2-trifluoromethyl-                                   
                                   OMe                                    
                     phenylsulfonyl                                       
1053  4-amidinophenyl                                                     
                     4-trifluoromethyl-                                   
                                   OMe                                    
                     phenylsulfonyl                                       
1054  4-amidinophenyl                                                     
                     2-fluorophenyl-                                      
                                   OMe                                    
                     sulfonyl                                             
1055  4-amidinophenyl                                                     
                     4-fluorophenyl-                                      
                                   OMe                                    
                     sulfonyl                                             
1056  4-amidinophenyl                                                     
                     4-methoxyphenyl-                                     
                                   OMe                                    
                     sulfonyl                                             
1057  4-amidinophenyl                                                     
                     2,3,4,5,6-tetramethyl-                               
                                   OMe                                    
                     phenylsulfonyl                                       
1058  4-amidinophenyl                                                     
                     4-cyanophenyl-                                       
                                   OMe                                    
                     sulfonyl                                             
1059  4-amidinophenyl                                                     
                     4-chlorophenyl-                                      
                                   OMe                                    
                     sulfonyl                                             
1060  4-amidinophenyl                                                     
                     4-ethylphenyl-                                       
                                   OMe                                    
                     sulfonyl                                             
1061  4-amidinophenyl                                                     
                     4-propylphenyl-                                      
                                   OMe                                    
                     sulfonyl                                             
1062  4-amidinophenyl                                                     
                     n-propylsulfonyl                                     
                                   OMe                                    
1063  4-amidinophenyl                                                     
                     2-phenylethyl-                                       
                                   OMe                                    
                     sulfonyl                                             
1064  4-amidinophenyl                                                     
                     4-isopropylphenyl-                                   
                                   OMe                                    
                     sulfonyl                                             
1065  4-amidinophenyl                                                     
                     3-phenylpropyl-                                      
                                   OMe                                    
                     sulfonyl                                             
1066  4-amidinophenyl                                                     
                     3-pyridylsulfonyl                                    
                                   OMe                                    
1068  4-amidinophenyl                                                     
                     2-pyridylsulfonyl                                    
                                   OMe                                    
1069  4-amidinophenyl                                                     
                     2,2-diphenyl-1-                                      
                                   OMe                                    
                     ethenylsulfonyl                                      
1070  4-amidinophenyl                                                     
                     2-pyrimidinyl-                                       
                                   OMe                                    
                     sulfonyl                                             
1071  4-amidinophenyl                                                     
                     4-methyl-2-   OMe                                    
                     pyrimidinylsulfonyl                                  
1072  4-amidinophenyl                                                     
                     4,6-dimethyl-2-                                      
                                   OMe                                    
                     pyrimidinylsulfonyl                                  
1073  4-amidinophenyl                                                     
                     1,2,4-triazol-3-                                     
                                   OMe                                    
                     ylsulfonyl                                           
1074  4-amidinophenyl                                                     
                     1-methyl-1,3,4-                                      
                                   OMe                                    
                     trizol-5-ylsulfonyl                                  
1075  4-amidinophenyl                                                     
                     3,5-dimethyl-4-                                      
                                   OMe                                    
                     pyrazolylsulfonyl                                    
1076  4-amidinophenyl                                                     
                     1-phenyl-4-   OMe                                    
                     pyrazolylsulfonyl                                    
1077  4-amidinophenyl                                                     
                     n-butylaminosulfonyl                                 
                                   OMe                                    
1078  4-amidinophenyl                                                     
                     i-butylaminosulfonyl                                 
                                   OMe                                    
1079  4-amidinophenyl                                                     
                     t-butylaminosulfonyl                                 
                                   OMe                                    
1080  4-amidinophenyl                                                     
                     i-propylamino-                                       
                                   OMe                                    
                     sulfonyl                                             
1081  4-amidinophenyl                                                     
                     cyclohexylamino-                                     
                                   OMe                                    
                     sulfonyl                                             
1082  4-amidinophenyl                                                     
                     phenylaminosulfonyl                                  
                                   OMe                                    
1083  4-amidinophenyl                                                     
                     benzylaminosulfonyl                                  
                                   OMe                                    
1084  4-amidinophenyl                                                     
                     dimethylamino-                                       
                                   OMe                                    
                     sulfonyl                                             
1085  4-amidino-2-fluoro-                                                 
                     3-methylphenyl-                                      
                                   OMe                                    
      phenyl         sulfonyl                                             
1086  2-amidino-5-pyridyl                                                 
                     n-butyloxycarbonyl                                   
                                   OMe                                    
1088  2-amidino-5-pyridyl                                                 
                     3-methylphenyl-                                      
                                   OMe                                    
                     sulfonyl                                             
1089  3-amidino-6-pyridyl                                                 
                     n-butyloxycarbonyl                                   
                                   OMe                                    
1090  3-amidino-6-pyridyl                                                 
                     3-methylphenyl-                                      
                                   OMe                                    
                     sulfonyl                                             
1091  4-amidinophenyl                                                     
                     phenylaminocarbonyl                                  
                                   OMe                                    
1092  4-amidinophenyl                                                     
                     4-fluorophenylamino-                                 
                                   OMe                                    
                     carbonyl                                             
1093  4-amidinophenyl                                                     
                     1-naphthylamino-                                     
                                   OMe                                    
                     carbonyl                                             
1094  4-amidinophenyl                                                     
                     benzylaminocarbonyl                                  
                                   OMe                                    
1095  4-amidinophenyl                                                     
                     n-butylaminocarbonyl                                 
                                   OMe                                    
1096  4-amidinophenyl                                                     
                     4-ethylphenyl-                                       
                                   OMe                                    
                     carbonyl                                             
1097  4-amidinophenyl                                                     
                     biphenylcarbonyl                                     
                                   OMe                                    
1098  4-amidinophenyl                                                     
                     2-naphthylcarbonyl                                   
                                   OMe                                    
1099  4-amidinophenyl                                                     
                     (2-chlorophenyl)                                     
                                   OMe                                    
                     methoxycarbonyl                                      
1100  4-amidinophenyl                                                     
                     (2-chlorophenyl)                                     
                                   OH                                     
                     methoxycaronyl                                       
1101  4-amidinophenyl                                                     
                     (2-bromophenyl)                                      
                                   OMe                                    
                     methoxycarbonyl                                      
1102  4-amidinophenyl                                                     
                     (2-bromophenyl)                                      
                                   OH                                     
                     methoxycarbonyl                                      
1103  4-amidinophenyl                                                     
                     n-hexyloxycarbonyl                                   
                                   OMe                                    
1104  4-amidinophenyl                                                     
                     n-hexyloxycarbonyl                                   
                                   OH                                     
1105  4-amidinophenyl                                                     
                     isobutyloxycarbonyl                                  
                                   OMe                                    
1106  4-amidinophenyl                                                     
                     isobutyloxycarbonyl                                  
                                   OH                                     
1107  4-amidinophenyl                                                     
                     2-cyclopropylethoxy-                                 
                                   OMe                                    
                     carbonyl                                             
1108  4-amidinophenyl                                                     
                     2-cyclopropylethoxy-                                 
                                   OH                                     
                     carbonyl                                             
1110  4-amidinophenyl                                                     
                     2-cyclopentylethoxy-                                 
                                   OMe                                    
                     carbonyl                                             
1111  4-amidinophenyl                                                     
                     2-cyclopentylethoxy-                                 
                                   OH                                     
                     carbonyl                                             
1112  4-amidinophenyl                                                     
                     4,4,4-trifluoro-                                     
                                   OMe                                    
                     butyloxycarbonyl                                     
1113  4-amidinophenyl                                                     
                     4,4,4-trifluoro-                                     
                                   OH                                     
                     butyloxycarbonyl                                     
1114  4-amidinophenyl                                                     
                     n-propylsulfonyl                                     
                                   OH                                     
1115  4-amidinophenyl                                                     
                     2-methylphenyl-                                      
                                   OMe                                    
                     sulfonyl                                             
1116  4-amidinophenyl                                                     
                     4-chloro-2,5-dimethyl-                               
                                   OH   536                               
                     phenylsulfonyl                                       
1117  4-amidinophenyl                                                     
                     2,3-dichlorophenyl-                                  
                                   OMe                                    
                     sulfonyl                                             
1118  4-amidinophenyl                                                     
                     2-bromophenyl-                                       
                                   OMe                                    
                     sulfonyl                                             
1119  4-amidinophenyl                                                     
                     3-bromophenyl-                                       
                                   OMe                                    
                     sulfonyl                                             
1120  4-amidinophenyl                                                     
                     4-bromophenyl-                                       
                                   OMe                                    
                     sulfonyl                                             
1121  4-amidinophenyl                                                     
                     biphenylsulfonyl                                     
                                   OMe                                    
1122  4-amidinophenyl                                                     
                     5-chloro-1,3- OMe                                    
                     dimethyl-4-pyrazolyl                                 
1123  4-amidinophenyl                                                     
                     3-bromo-2-    OMe                                    
                     thienylsulfonyl                                      
1124  4-amidinophenyl                                                     
                     5-bromo-2-    OMe                                    
                     thienylsulfonyl                                      
1125  4-amidinophenyl                                                     
                     5-[1-methyl-5-                                       
                                   OMe                                    
                     trifluoromethyl-3-                                   
                     pyrazolyl]-2-                                        
                     thienylsulfonyl                                      
1127  4-amidinophenyl                                                     
                     5-(3-isoxazolyl)-2-                                  
                                   OMe                                    
                     thienylsulfonyl                                      
1128  4-amidinophenyl                                                     
                     5-(2-pyridinyl)-2-                                   
                                   OMe                                    
                     thienylsulfonyl                                      
1129  4-amidinophenyl                                                     
                     4-methyl-2-   OMe                                    
                     methylcarbonylamino-                                 
                     5-thiazolylsulfonyl                                  
1130  4-amidinophenyl                                                     
                     2-benzothienyl-                                      
                                   OMe                                    
                     sulfonyl                                             
1131  4-amidinophenyl                                                     
                     2-benzothienyl-                                      
                                   OMe                                    
                     sulfonyl                                             
1132  4-amidinophenyl                                                     
                     3-methyl-2-   OMe                                    
                     benzothienylsulfonyl                                 
1133  4-amidinophenyl                                                     
                     8-quinolinylsulfonyl                                 
                                   OMe                                    
1134  4-amidinophenyl                                                     
                     8-quinolinylsulfonyl                                 
                                   OH                                     
1135  4-amidinophenyl                                                     
                     2,1,3-benzo-  OMe                                    
                     thiadiazol-4-ylsulfonyl                              
1136  4-amidinophenyl                                                     
                     2,1,3-benzo-  OH                                     
                     thiadiazol-4-ylsulfonyl                              
1137  4-amidinophenyl                                                     
                     4-N,N-dimethylamino-                                 
                                   OMe                                    
                     1-naphthylsulfonyl                                   
1138  4-amidinophenyl                                                     
                     4-N,N-dimethylamino-                                 
                                   OH                                     
                     1-haphthylsulfonyl                                   
1139  4-amidinophenyl                                                     
                     2,1,3-benzoxadiazol-4-                               
                                   OMe                                    
                     ylsulfonyl                                           
1140  4-amidinophenyl                                                     
                     2,1,3-benzoxadiazol-4-                               
                                   OH                                     
                     ylsulfonyl                                           
1141  4-amidinophenyl                                                     
                     2,2,5,7,8-pentamethyl                                
                                   OMe                                    
                     3,4-dihydro-2Hbenxo-                                 
                     pyran-6-ylsulfonyl                                   
1143  4-amidinophenyl                                                     
                     2,2,5,7,8-pentamethyl                                
                                   OH                                     
                     3,4-dihydro-2Hbenzo-                                 
                     pyran-6-ylsulfonyl                                   
1144  4-N-methylamidino                                                   
                     3-            OMe                                    
      phenyl         methylphenylsulfonyl                                 
1145  4-N-ethylamidino                                                    
                     3-            OMe                                    
      phenyl         methylphenylsulfonyl                                 
1146  4-N-n-propylamidino                                                 
                     3-            OMe                                    
      phenyl         methylphenylsulfonyl                                 
1147  4-N-benzylamidino                                                   
                     3-            OMe                                    
      phenyl         methylphenylsulfonyl                                 
1148  4-N-n-butylamidino                                                  
                     3-            OMe                                    
      phenyl         methylphenylsulfonyl                                 
1149  4-N-methylamidino                                                   
                     3-            OH                                     
      phenyl         methylphenylsulfonyl                                 
1150  4-N-ethylamidino                                                    
                     3-            OH                                     
      phenyl         methylphenylsulfonyl                                 
1151  4-N-n-propylamidino                                                 
                     3-            OH                                     
      phenyl         methylphenylsulfonyl                                 
1152  4-N-benzylamidino                                                   
                     3-            OH                                     
      phenyl         methylphenylsulfonyl                                 
1153  4-N-n-butylamidino                                                  
                     3-            OH                                     
      phenyl         methylphenylsulfonyl                                 
1154  4-N-methylamidino-                                                  
                     n-butyloxycarbonyl                                   
                                   OMe                                    
      phenyl                                                              
1155  4-N-ethylamidinophenyl                                              
                     n-butyloxycarbonyl                                   
                                   OMe                                    
1156  4-N-npropylamidino-                                                 
                     n-butyloxycarbonyl                                   
                                   OMe                                    
      phenyl                                                              
1157  4-N-n-butylamidino-                                                 
                     n-butyloxycarbonyl                                   
                                   OMe                                    
      phenyl                                                              
1158  4-N-benzylamidino-                                                  
                     n-butyloxycarbonyl                                   
                                   OMe                                    
      phenyl                                                              
1160  4-N-methylamidino-                                                  
                     n-butyloxycarbonyl                                   
                                   OH                                     
      phenyl                                                              
1161  4-N-ethylamidino-                                                   
                     n-butyloxycarbonyl                                   
                                   OH                                     
      phenyl                                                              
1162  4-N-n-propylamidino-                                                
                     n-butyloxycarbonyl                                   
                                   OH                                     
      phenyl                                                              
1163  4-N-n-butylamidino-                                                 
                     n-butyloxycarbonyl                                   
                                   OH                                     
      phenyl                                                              
1164  4-N-benzylamidino-                                                  
                     n-butyloxycarbonyl                                   
                                   OH                                     
      phenyl                                                              
1165  4-(acetoxyamidino)-                                                 
                     n-butyloxycarbonyl                                   
                                   OMe                                    
      phenyl                                                              
1166  4-(acetoxyamidino)-                                                 
                     n-butyloxycarbonyl                                   
                                   OH                                     
      phenyl                                                              
1167  4-(acetoxyamidino)-                                                 
                     isobutyloxycarbonyl                                  
                                   OMe                                    
      phenyl                                                              
1168  4-(acetoxyamidino)-                                                 
                     isobutyloxycarbonyl                                  
                                   OH                                     
      phenyl                                                              
1169  4-(acetoxyamidino)-                                                 
                     cyclopropylethoxy-                                   
                                   OMe                                    
      phenyl         carbonyl                                             
1170  4-(acetoxyamidino)-                                                 
                     cyclopropylethoxy-                                   
                                   OH                                     
      phenyl         carbonyl                                             
1171  4-(acetoxyamidino)-                                                 
                     benzyloxycarboyl                                     
                                   OMe                                    
      phenyl                                                              
1172  4-(acetoxyamidino)-                                                 
                     benzyloxycarbonyl                                    
                                   OH                                     
      phenyl                                                              
1173  4-(acetoxyamidino)-                                                 
                     4-            OMe                                    
      phenyl         methylphenylsulfonyl                                 
1174  4-(acetoxyamidino)-                                                 
                     4-            OH                                     
      phenyl         methylphenylsulfonyl                                 
1175  4-piperidinylethyl                                                  
                     n-butyloxycarbonyl                                   
                                   OMe                                    
1176  4-piperidinylethyl                                                  
                     benzyloxycarbonyl                                    
                                   OMe                                    
1177  4-piperidinylethyl                                                  
                     n-propyloxycarbonyl                                  
                                   OMe                                    
1178  4-piperidinylethyl                                                  
                     isobutyloxycarbonyl                                  
                                   OMe                                    
1179  4-piperidinylethyl                                                  
                     2-            OMe                                    
                     methylphenylsulfonyl                                 
1180  4-piperidinylethyl                                                  
                     3-            OMe                                    
                     methylphenylsulfonyl                                 
1181  4-piperidinylethyl                                                  
                     4-            OMe                                    
                     methylphenylsulfonyl                                 
1182  4-piperidinylethyl                                                  
                     2-            OMe                                    
                     bromophenylsulfonyl                                  
1183  4-piperidinylethyl                                                  
                     3-            OMe                                    
                     bromophenylsulfonyl                                  
1184  4-piperidinylethyl                                                  
                     2-methoxy-                                           
                     phenylsulfonyl                                       
1185  4-piperidinylethyl                                                  
                     3-methoxy-    OMe                                    
                     phenylsulfonyl                                       
1186  4-piperidinylethyl                                                  
                     3-            OMe                                    
                     trifluoromethylphenyl                                
                     sulfonyl                                             
1187  4-piperidinylethyl                                                  
                     n-propylsulfonyl                                     
                                   OMe                                    
1188  4-piperidinylethyl                                                  
                     n-butylsulfonyl                                      
                                   OMe                                    
1189  4-piperidinylethyl                                                  
                     isopropylsulfonyl                                    
                                   OMe                                    
1190  4-piperidinylethyl                                                  
                     isobutylsulfonyl                                     
                                   OMe                                    
1191  4-piperidinylethyl                                                  
                     3,5-dimethyl- OMe                                    
                     isoxazolylsulfonyl                                   
1192  4-piperidinylethyl                                                  
                     2,4-dimethyl- OMe                                    
                     thiazolylsulfonyl                                    
1193  4-piperidinylpropyl                                                 
                     n-butyloxycarbonyl                                   
                                   OMe                                    
1194  4-piperidinylpropyl                                                 
                     n-propyloxycarbonyl                                  
                                   OMe                                    
1195  4-piperidinylpropyl                                                 
                     benzyloxycarbonyl                                    
                                   OMe                                    
1196  4-piperidinylpropyl                                                 
                     isobutyloxycarbonyl                                  
                                   OMe                                    
1197  4-piperidinylpropyl                                                 
                     2-methylphenyl-                                      
                                   OMe                                    
                     sulfonyl                                             
1198  4-piperidinylpropyl                                                 
                     3-methylphenyl-                                      
                                   OMe                                    
                     sulfonyl                                             
1199  4-piperidinylpropyl                                                 
                     4-methylphenyl-                                      
                                   OMe                                    
                     sulfonyl                                             
1200  4-piperidinylpropyl                                                 
                     2-            OMe                                    
                     bromophenylsulfonyl                                  
1201  4-piperidinylpropyl                                                 
                     n-butylsulfonyl                                      
                                   OMe                                    
1202  4-piperidinylpropyl                                                 
                     isobutylsulfonyl                                     
                                   OMe                                    
1203  4-piperidinylpropyl                                                 
                     3,5-dimethyl- OMe                                    
                     isoxazolylsulfonyl                                   
1204  4-piperidinylpropyl                                                 
                     2,4-dimethyl- OMe                                    
                     thiazoylsulfonyl                                     
1205  4-piperidinylethyl                                                  
                     n-butyloxycarbonyl                                   
                                   OH                                     
1206  4-piperidinylethyl                                                  
                     n-propyloxycarbonyl                                  
                                   OH                                     
1207  4-piperidinylethyl                                                  
                     benyloxycarbonyl                                     
                                   OH                                     
1208  4-piperidinylethyl                                                  
                     isobutyloxycarbonyl                                  
                                   OH                                     
1209  4-piperidinylethyl                                                  
                     2-methylphenyl-                                      
                                   OH                                     
                     sulfonyl                                             
1210  4-piperidinylethyl                                                  
                     3-methylphenyl-                                      
                                   OH                                     
                     sulfonyl                                             
1211  4-piperidinylethyl                                                  
                     4-methylphenyl-                                      
                                   OH                                     
                     sulfonyl                                             
1212  4-piperidinylethyl                                                  
                     2-            OH                                     
                     bromophenylsulfonyl                                  
1213  4-piperidinylethyl                                                  
                     3,5-dimethyl- OH                                     
                     isoxazolylsulfonyl                                   
1214  4-piperidinylethyl                                                  
                     2,4-dimethyl- OH                                     
                     thiazolylsulfonyl                                    
1215  4-piperidinylethyl                                                  
                     n-butylsulfonyl                                      
                                   OH                                     
1216  4-piperidinylethyl                                                  
                     isobutylsulfonyl                                     
                                   OH                                     
1217  4-piperidinylpropyl                                                 
                     n-butyloxycarbonyl                                   
                                   OH                                     
1218  4-piperidinylpropyl                                                 
                     n-propyloxycarbonyl                                  
                                   OH                                     
1219  4-piperidinylpropyl                                                 
                     isobutyloxycarbonyl                                  
                                   OH                                     
1220  4-piperidinylpropyl                                                 
                     2-methylphenyl-                                      
                                   OH                                     
                     carbonyl                                             
1221  4-piperidinylpropyl                                                 
                     4-methylphenyl-                                      
                                   OH                                     
                     carbonyl                                             
1222  4-piperidinylpropyl                                                 
                     2-bromophenyl-                                       
                                   OH                                     
                     carbonyl                                             
1223  4-piperidinylpropyl                                                 
                     3,5-dimethyl- OH                                     
                     isoxazolylsulfonyl                                   
1224  4-piperidinylpropyl                                                 
                     n-butylsulfonyl                                      
                                   OH                                     
1225  4-piperidinylpropyl                                                 
                     isobutylsulfonyl                                     
                                   OH                                     
1226  4-amidinopiperidinyl                                                
                     n-butyloxycarbonyl                                   
                                   OMe                                    
1227  4-amidinopiperidinyl                                                
                     isobutyloxycarbonyl                                  
                                   OMe                                    
1228  4-amidinopiperidinyl                                                
                     n-propyloxycarbonyl                                  
                                   OMe                                    
1229  4-amidinopiperidinyl                                                
                     benzyloxycarbonyl                                    
                                   OMe                                    
1230  4-amidinopiperidinyl                                                
                     n-butylsulfonyl                                      
                                   OMe                                    
1231  4-amidinopiperidinyl                                                
                     isobutylsulfonyl                                     
                                   OMe                                    
1232  4-amidinopiperidinyl                                                
                     n-propylsulfonyl                                     
                                   OMe                                    
1233  4-amidinopiperidinyl                                                
                     2-methylphenyl-                                      
                                   OMe                                    
                     sulfonyl                                             
1234  4-amidinopiperidinyl                                                
                     4-methylphenyl-                                      
                                   OMe                                    
                     sulfonyl                                             
1235  4-amidinopiperidinyl                                                
                     benzylsulfonyl                                       
                                   OMe                                    
1236  4-amidinopiperidinyl                                                
                     3,5-dimethyl- OMe                                    
                     isoxazolylsulfonyl                                   
1237  4-amidinopiperidinyl                                                
                     2,4-dimethyl- OMe                                    
                     thiazolylsulfonyl                                    
1238  4-amidinopiperidinyl                                                
                     4-methylphenyl-                                      
                                   OH                                     
                     sulfonyl                                             
1239  4-amidinopiperidinyl                                                
                     n-butyloxycarbonyl                                   
                                   OH                                     
1240  4-amidinopiperidinyl                                                
                     isobutyloxycarbonyl                                  
                                   OH                                     
1241  4-amidinopiperidinyl                                                
                     n-propyloxycarbonyl                                  
                                   OH                                     
1242  4-amidinopiperidinyl                                                
                     benzyloxycarbonyl                                    
                                   OH                                     
1243  4-amidinopiperidinyl                                                
                     n-butylsulfonyl                                      
                                   OH                                     
1244  4-amidinopiperidinyl                                                
                     isobutylsulfonyl                                     
                                   OH                                     
1245  4-amidinopiperidinyl                                                
                     2-methylphenyl-                                      
                                   OH                                     
                     sulfonyl                                             
1246  4-amidinopiperidinyl                                                
                     3-methylphenyl-                                      
                                   OH                                     
                     sulfonyl                                             
1247  4-amidinopiperidinyl                                                
                     4-methylphenyl-                                      
                                   OH                                     
                     sulfonyl                                             
1248  4-amidinopiperidinyl                                                
                     2-            OH                                     
                     bromophenylsulfonyl                                  
1249  4-amidinopiperidinyl                                                
                     3-            OH                                     
                     bromophenylsulfonyl                                  
1250  4-amidinopiperidinyl                                                
                     3,5-dimethyl- OH                                     
                     isoxazolylsulfonyl                                   
1251  4-amidinopiperidinyl                                                
                     2,4-dimethyl- OH                                     
                     thiazolylsulfonyl                                    
1252  4-amidino-     n-butyloxycarbonyl                                   
                                   OMe                                    
      piperidinylmethyl                                                   
1253  4-amidino-     n-propyloxycarbonyl                                  
                                   OMe                                    
      piperidinylmethyl                                                   
1254  4-amidino-     benzyloxycarbonyl                                    
                                   OMe                                    
      piperidinylmethyl                                                   
1255  4-amidino-     n-butylsulfonyl                                      
                                   OMe                                    
      piperidinylmethyl                                                   
1256  4-amidino-     n-propylsulfonyl                                     
                                   OMe                                    
      piperidinylmethyl                                                   
1257  4-amidino-     2-methylphenyl-                                      
                                   OMe                                    
      piperidinylmethyl                                                   
                     sulfonyl                                             
1258  4-amidino-     3-methylphenyl-                                      
                                   OMe                                    
      piperidinylmethyl                                                   
                     sulfonyl                                             
1259  4-amidino-     4-methylphenyl-                                      
                                   OMe                                    
      piperidinylmethyl                                                   
                     sulfonyl                                             
1260  4-amidino-     2-            OMe                                    
      piperidinylmethyl                                                   
                     bromophenylsulfonyl                                  
1261  4-amidino-     3-            OMe                                    
      piperidinylmethyl                                                   
                     bromophenylsulfonyl                                  
1262  4-amidino-     3,5-dimethyl- OMe                                    
      piperidinylmethyl                                                   
                     isoxazolylsulfonyl                                   
1263  4-amidino-     4-methylphenyl-                                      
                                   OH                                     
      piperidinylmethyl                                                   
                     sulfonyl                                             
1264  4-amidino-     n-butyloxycarbonyl                                   
                                   OH                                     
      piperidinylmethyl                                                   
1265  4-amidino-     n-propyloxycarbonyl                                  
                                   OH                                     
      piperidinylmethyl                                                   
1266  4-amidino-     benzyloxycarbonyl                                    
                                   OH                                     
      piperidinylmethyl                                                   
1267  4-amidino-     n-butylsulfonyl                                      
                                   OH                                     
      piperidinylmethyl                                                   
1268  4-amidino-     2-methylphenyl-                                      
                                   OH                                     
      piperidinylmethyl                                                   
                     sulfonyl                                             
1269  4-amidino-     3-methylphenyl-                                      
                                   OH                                     
      piperidinylmethyl                                                   
                     sulfonyl                                             
1270  4-amidino-     2-bromophenyl-                                       
                                   OH                                     
      piperidinylmethyl                                                   
                     sulfonyl                                             
1271  4-amidino-     3-bromophenyl-                                       
                                   OH                                     
      piperidinylmethyl                                                   
                     sulfonyl                                             
1272  4-amidino-     3,5-dimethyl- OH                                     
      piperidinylmethyl                                                   
                     isoxazolylsulfonyl                                   
1273  4-quinuclidinylethyl                                                
                     n-butyloxycarbonyl                                   
                                   OH                                     
1274  4-quinuclidinylethyl                                                
                     n-propyloxycarbonyl                                  
                                   OH                                     
1275  4-quinuclidinylethyl                                                
                     benzyloxycarbonyl                                    
                                   OH                                     
1276  4-quinuclidinylethyl                                                
                     n-butylsulfonyl                                      
                                   OH                                     
1277  4-quinuclidinylethyl                                                
                     2-methylphenyl-                                      
                                   OH                                     
                     sulfonyl                                             
1278  4-quinuclidinylethyl                                                
                     4-methylphenyl-                                      
                                   OH                                     
                     sulfonyl                                             
1279  4-quinuclidinylethyl                                                
                     2-            OH                                     
                     bromophenylsulfonyl                                  
1280  4-quinuclidinylethyl                                                
                     3-            OH                                     
                     bromophenylsulfonyl                                  
1281  4-quinuclidinylethyl                                                
                     3,5-dimethyl- OH                                     
                     isoxazolylsulfonyl                                   
1282  guanidinopropyl                                                     
                     n-butyloxycarbonyl                                   
                                   OMe                                    
1283  guanidinopropyl                                                     
                     n-propyloxycarbonyl                                  
                                   OMe                                    
1284  guanidinopropyl                                                     
                     benzyloxycarbonyl                                    
                                   OH   435                               
1285  guanidinopropyl                                                     
                     n-butylsulfonyl                                      
                                   OMe                                    
1286  guanidinopropyl                                                     
                     2-methylphenyl-                                      
                                   OMe                                    
                     sulfonyl                                             
1287  guanidinopropyl                                                     
                     3-methylphenyl-                                      
                                   OMe                                    
                     sulfonyl                                             
1288  guanidinopropyl                                                     
                     2-            OMe                                    
                     bromophenylsulfonyl                                  
1289  guanidinopropyl                                                     
                     3-            OMe                                    
                     bromophenylsulfonyl                                  
1290  guanidinopropyl                                                     
                     3,5-dimethyl- OMe                                    
                     isoxazolylsulfonyl                                   
1291  guanidinopropyl                                                     
                     benzylsulfonyl                                       
                                   OMe                                    
1292  guanidinopropyl                                                     
                     styrylsulfonyl                                       
                                   OMe                                    
1293  guanidinopropyl                                                     
                     2-benzothiophene-                                    
                                   OMe                                    
                     sulfonyl                                             
1294  guanidinopropyl                                                     
                     n-butyloxycarbonyl                                   
                                   OH                                     
1295  guanidinopropyl                                                     
                     n-propyloxycarbonyl                                  
                                   OH                                     
1296  guanidinopropyl                                                     
                     benzyloxycarbonyl                                    
                                   OH                                     
1297  guanidinopropyl                                                     
                     n-butylsulfonyl                                      
                                   OH                                     
1298  guanidinopropyl                                                     
                     2-methylphenyl-                                      
                                   OH                                     
                     sulfonyl                                             
1299  guanidinopropyl                                                     
                     3-methylphenyl-                                      
                                   OH                                     
                     sulfonyl                                             
1300  guanidinopropyl                                                     
                     4-methylphenyl-                                      
                                   OH                                     
                     sulfonyl                                             
1301  guanidinopropyl                                                     
                     2-            OH                                     
                     bromophenylsulfonyl                                  
1302  guanidinopropyl                                                     
                     3-            OH                                     
                     bromophenylsulfonyl                                  
1303  guanidinopropyl                                                     
                     3,5-dimethyl- OH                                     
                     isoxazolylsulfonyl                                   
1304  guanidinopropyl                                                     
                     2,4-dimethyl- OH                                     
                     thiazolylsulfonyl                                    
1305  guanidinopropyl                                                     
                     benzylsulfonyl                                       
                                   OH                                     
1306  guanidinopropyl                                                     
                     styrylsulfonyl                                       
                                   OH                                     
1307  guanidinopropyl                                                     
                     2-benzothiophene-                                    
                                   OH                                     
                     sulfonyl                                             
1308  guanidinobutyl n-butyloxycarbonyl                                   
                                   OH                                     
1309  guanidinobutyl n-butylsulfonyl                                      
                                   OH                                     
1310  guanidinobutyl phenylsulfonyl                                       
                                   OH                                     
1311  guanidinobutyl 2-methylphenyl-                                      
                                   OH                                     
                     sulfonyl                                             
1312  guanidinobutyl 4-methylphenyl-                                      
                                   OH                                     
                     sulfonyl                                             
1313  guanidinobutyl 2-            OH                                     
                     bromophenylsulfonyl                                  
1314  guanidinobutyl 3,5-dimethyl- OH                                     
                     isoxazolylsulfonyl                                   
1315  guanidinobutyl 2,4-dimethyl- OH                                     
                     thiazolylsulfonyl                                    
1316  guanidinobutyl benzylsulfonyl                                       
                                   OH                                     
1317  guanidinobutyl styrylsulfonyl                                       
                                   OH                                     
1318  guanidinobutyl 3-fluorophenyl-                                      
                                   OH                                     
                     sulfonyl                                             
1319  guanidinobutyl n-butyloxycarbonyl                                   
                                   OMe                                    
1320  guanidinobutyl n-butylsulfonyl                                      
                                   OMe                                    
1321  guanidinobutyl benzyloxycarbonyl                                    
                                   OH   449                               
1322  guanidinobutyl phenylsulfonyl                                       
                                   OMe                                    
1323  guanidinobutyl 2-methylphenyl-                                      
                                   OMe                                    
                     sulfonyl                                             
1324  guanidinobutyl 2-            OMe                                    
                     bromophenylsulfonyl                                  
1325  guanidinobutyl 3-            OMe                                    
                     bromophenylsulfonyl                                  
1326  guanidinobutyl 3,5-dimethyl- OMe                                    
                     isoxazolyl sufonyl                                   
1327  guanidinobutyl benzylsulfonyl                                       
                                   OMe                                    
1328  guanidinobutyl n-butyloxycarbonyl                                   
                                   OH                                     
1329  guanidinobutyl isobutyloxycarbonyl                                  
                                   OH                                     
1330  guanidinobutyl n-propyloxycarbonyl                                  
                                   OH                                     
1331  guanidinobutyl phenylsulfonyl                                       
                                   OH                                     
1332  guanidinobutyl n-butylsulfonyl                                      
                                   OH                                     
1333  guanidinobutyl 2-methylphenyl-                                      
                                   OH                                     
                     sulfonyl                                             
1334  guanidinobutyl 3-methylphenyl-                                      
                                   OH                                     
                     sulfonyl                                             
1335  guanidinobutyl 4-methylphenyl-                                      
                                   OH                                     
                     sulfonyl                                             
1336  guanidinobutyl 2-            OH                                     
                     bromophenylsulfonyl                                  
1337  4-piperidinylmethyl-                                                
                     n-butyloxycarbonyl                                   
                                   OH                                     
      aminocarbonyl                                                       
1338  4-piperidinylmethyl-                                                
                     n-butyloxycarbonyl                                   
                                   OMe                                    
      amino-carbonyl                                                      
1339  4-piperidinylmethyl-                                                
                     benzyloxycarbonyl                                    
                                   OH                                     
      amino-carbonyl                                                      
1340  4-piperidinylmethyl-                                                
                     benzyloxycarbonyl                                    
                                   OMe                                    
      amino-carbonyl                                                      
1341  4-piperidinylmethyl-                                                
                     n-butylsulfonyl                                      
                                   OH                                     
      amino-carbonyl                                                      
1342  4-piperidinylmethyl-                                                
                     n-butylsulfonyl                                      
                                   OMe                                    
      amino-carbonyl                                                      
1343  4-piperidinylmethyl-                                                
                     2-methylphenyl-                                      
                                   OH                                     
      amino-carbonyl sulfonyl                                             
1344  4-piperidinylmethyl-                                                
                     2-methylphenyl-                                      
                                   OMe                                    
      amino-carbonyl sulfonyl                                             
1345  4-piperidinylmethyl-                                                
                     3-methylphenyl-                                      
                                   OH                                     
      amino-carobnyl sulfonyl                                             
1346  4-piperidinylmethyl-                                                
                     4-methylphenyl-                                      
                                   OH                                     
      amino-carbonyl sulfonyl                                             
1347  4-piperidinylmethyl-                                                
                     3-methylphenyl-                                      
                                   OMe                                    
      amino-carbonyl sulfonyl                                             
1348  4-piperidinylmethyl-                                                
                     3,5-dimethyl- OH                                     
      amino-carbonyl isoxazolylsulfonyl                                   
1349  4-piperidinylmethyl-                                                
                     3,5-dimethyl- OMe                                    
      amino-carbonyl isoxazolylsulfonyl                                   
1350  N-(4-piperidinyl-                                                   
                     n-butyloxycarbonyl                                   
                                   OH                                     
      methyl)-N-methyl-                                                   
      aminocarbonyl                                                       
1351  N-(4-piperidinyl-                                                   
                     n-butyloxycarbonyl                                   
                                   OMe                                    
      methyl)-N-methyl-                                                   
      aminocarbonyl                                                       
1352  N-(4-piperdinyl-                                                    
                     benzyloxycarbonyl                                    
                                   OH                                     
      methyl)-N-methyl-                                                   
      aminocarbonyl                                                       
1353  N-(4-piperidinyl-                                                   
                     benzyloxycarbonyl                                    
                                   OMe                                    
      methyl)-N-methyl-                                                   
      aminocarbonyl                                                       
1354  N-(4-piperidinyl-                                                   
                     n-butylsulfonyl                                      
                                   OH                                     
      methyl)-N-methyl-                                                   
      aminocarbonyl                                                       
1355  N-(4-piperidinyl-                                                   
                     n-butylsulfonyl                                      
                                   OMe                                    
      methyl)-N-                                                          
      methylaminocarbonyl                                                 
1356  N-(4-piperidinyl-                                                   
                     2-methylphenyl-                                      
                                   OH                                     
      methyl)-N-methyl-                                                   
                     sulfonyl                                             
      aminocarbonyl                                                       
1357  N-(4-piperidinyl-                                                   
                     2-methylphenyl-                                      
                                   OMe                                    
      methyl)-N-methyl-                                                   
                     sulfonyl                                             
      aminocarbonyl                                                       
1358  N-(4-piperidinyl-                                                   
                     3-methylphenyl-                                      
                                   OH                                     
      methyl)-N-methyl-                                                   
                     sulfonyl                                             
      aminocarbonyl                                                       
1359  N-(4-N-piperidinyl-                                                 
                     4-methylphenyl-                                      
                                   OH                                     
      methyl)-N-methyl-                                                   
                     sulfonyl                                             
      aminocarbonyl                                                       
1360  N-(4-piperidinyl-                                                   
                     3-methylphenyl-                                      
                                   OMe                                    
      methyl)-N-methyl-                                                   
                     sulfonyl                                             
      aminocarbonyl                                                       
1361  N-(4-piperidinyl-                                                   
                     3,5-dimethyl- OH                                     
      methyl)-N-methyl-                                                   
                     isoxazolylsulfonyl                                   
      aminocarbonyl                                                       
1362  N-(4-piperidinyl-                                                   
                     3,5-dimethyl- OMe                                    
      methyl)-N-methyl-                                                   
                     isoxazolylsulfonyl                                   
      aminocarbonyl                                                       
1363  4-piperidinyl- n-butyloxycarbonyl                                   
                                   OH                                     
      aminocarbonyl                                                       
1364  4-piperidinyl- 4-methylphenyl-                                      
                                   OH                                     
      aminocarbonyl  sulfonyl                                             
1365  4-guanidinophenyl                                                   
                     2-methylphenyl-                                      
                                   OH                                     
                     sulfonyl                                             
1366  4-guanidinophenyl                                                   
                     2-methylphenyl-                                      
                                   OMe                                    
                     sulfonyl                                             
1367  4-guanidinophenyl                                                   
                     2-            OH                                     
                     bromophenylsulfonyl                                  
1368  4-guanidinophenyl                                                   
                     2-            OMe                                    
                     bromophenylsulfonyl                                  
1369  4-guanidinophenyl                                                   
                     3-methylphenyl-                                      
                                   OH                                     
                     sulfonyl                                             
1370  4-guanidinophenyl                                                   
                     3,5-dimethyl- OH                                     
                     isoxazolylsulfonyl                                   
1371  4-guanidinophenyl                                                   
                     3,5-dimethyl- OMe                                    
                     isoxazolylsulfonyl                                   
1372  4-guanidinophenyl                                                   
                     2,4-dimethyl- OH                                     
                     thiazolylsulfonyl                                    
1373  4-guanidinophenyl                                                   
                     2,4-dimethyl- OMe                                    
                     thiazolylsulfonyl                                    
1374  4-guanidinophenyl                                                   
                     benzylsulfonyl                                       
                                   OH                                     
1375  4-guanidinophenyl                                                   
                     benzylsulfonyl                                       
                                   OMe                                    
1376  4-guanidinophenyl                                                   
                     styrylsulfonyl                                       
                                   OH                                     
1377  4-guanidinophenyl                                                   
                     styrylsulfonyl                                       
                                   OMe                                    
1378  4-guanidinophenyl                                                   
                     2-benzothiophene-                                    
                                   OH                                     
                     sulfonyl                                             
1379  3-guanidinophenyl                                                   
                     n-butyloxycarbonyl                                   
                                   OH                                     
1380  3-guanidinophenyl                                                   
                     n-butyloxycarbonyl                                   
                                   OMe                                    
1381  3-guanidinophenyl                                                   
                     n-propyloxycarbonyl                                  
                                   OH                                     
1382  3-guanidinophenyl                                                   
                     2-            OH                                     
                     bromophenylsulfonyl                                  
1383  3-guanidinophenyl                                                   
                     2-            OMe                                    
                     bromophenylsulfonyl                                  
1384  3-guanidinophenyl                                                   
                     2-methylphenyl-                                      
                                   OH                                     
                     sulfonyl                                             
1385  3-guanidinophenyl                                                   
                     4-methylphenyl-                                      
                                   OH                                     
                     sulfonyl                                             
1386  3-guanidinophenyl                                                   
                     4-methylphenyl-                                      
                                   OMe                                    
                     sulfonyl                                             
1387  3-guanidinophenyl                                                   
                     n-butylsulfonyl                                      
                                   OH                                     
1388  3-guanidinophenyl                                                   
                     n-butylsulfonyl                                      
                                   OMe                                    
1389  3-guanidinophenyl                                                   
                     styrylsulfonyl                                       
                                   OH                                     
1390  3-guanidinophenyl                                                   
                     benzyloxycarbonyl                                    
                                   OH                                     
1391  3-guanidinophenyl                                                   
                     benzyloxycarbonyl                                    
                                   OMe                                    
1392  4-amidinophenylmethyl                                               
                     2-methylphenyl-                                      
                                   OH                                     
                     sulfonyl                                             
1393  4-amidinophenylmethyl                                               
                     2-methylphenyl-                                      
                                   OMe                                    
                     sulfonyl                                             
1394  4-amidinophenylmethyl                                               
                     phenylsulfonyl                                       
                                   OH                                     
1395  4-amidinophenylmethyl                                               
                     phenylsulfonyl                                       
                                   OMe                                    
1396  4-amidinophenylmethyl                                               
                     3,5-dimethyl- OH                                     
                     isoxazolylsulfonyl                                   
1397  4-amidinophenylmethyl                                               
                     3,5-dimethyl- OMe                                    
                     isoxazolylsulfonyl                                   
1398  4-amidinophenylmethyl                                               
                     2,4-dimethyl- OH                                     
                     thiazolylsulfonyl                                    
1399  4-amidinophenylmethyl                                               
                     2,4-dimethyl- OMe                                    
                     thiazolylsulfonyl                                    
1400  4-amidinophenylmethyl                                               
                     p-toluylsulfonyl                                     
                                   OH                                     
1401  3-amidinophenylmethyl                                               
                     n-butyloxycarbonyl                                   
                                   OH                                     
1402  3-amidinophenylmethyl                                               
                     n-butyloxycarbonyl                                   
                                   OMe                                    
1403  3-amidinophenylmethyl                                               
                     phenylsulfonyl                                       
                                   OH                                     
1404  3-amidinophenylmethyl                                               
                     phenylsulfonyl                                       
                                   OMe                                    
1405  3-amidinophenylmethyl                                               
                     2-            OH                                     
                     bromophenylsulfonyl                                  
1406  3-amidinophenylmethyl                                               
                     2-            OMe                                    
                     bromophenylsulfonyl                                  
1407  3-amidinophenylmethyl                                               
                     2-methylphenyl-                                      
                                   OH                                     
                     sulfonyl                                             
1408  3-amidinophenylmethyl                                               
                     2-methylphenyl-                                      
                                   OMe                                    
                     sulfonyl                                             
1409  3-amidinophenylmethyl                                               
                     4-methylphenyl-                                      
                                   OH                                     
                     sulfonyl                                             
1410  3-amidinophenylmethyl                                               
                     4-methylphenyl-                                      
                                   OMe                                    
                     sulfonyl                                             
1411  3-amidinophenylmethyl                                               
                     styrylsulfonyl                                       
                                   OH                                     
1412  3-amidinophenylmethyl                                               
                     styrylsulfonyl                                       
                                   OMe                                    
1413  3-amidinophenylmethyl                                               
                     benzyloxycarbonyl                                    
                                   OH                                     
1414  3-amidinophenylmethyl                                               
                     benzyloxycarbonyl                                    
                                   OMe                                    
1415  3-amidinophenylmethyl                                               
                     3,5-dimethyl- OH                                     
                     isoxazolylsulfonyl                                   
1416  3-amidinophenylmethyl                                               
                     3,5-dimethyl- OMe                                    
                     isoxazolylsulfonyl                                   
1417  3-amidinophenylmethyl                                               
                     2,4-dimethyl- OH                                     
                     thiazolylsulfonyl                                    
1418  3-amidinophenylmethyl                                               
                     benzylsulfonyl                                       
                                   OH                                     
1419  4-pyridylethyl n-benzyloxycarbonyl                                  
                                   OMe                                    
1420  4-pyridylethyl n-benzyloxycarbonyl                                  
                                   OH                                     
1421  4-pyridylethyl n-butyloxyoxycarbonyl                                
                                   OMe                                    
1422  4-pyridylethyl n-butyloxyoxycarbonyl                                
                                   OH                                     
1423  4-pyridylethyl 2-            OH                                     
                     methylphenylsulfonyl                                 
1424  4-pyridylethyl 2-methylphenyl-                                      
                                   OMe                                    
                     sulfonyl                                             
1425  4-pyridylethyl 2-            OH                                     
                     bromophenylsulfonyl                                  
1426  4-pyridylethyl 2-            OMe                                    
                     bromophenylsulfonyl                                  
1427  4-pyridylethyl 3-methylphenyl-                                      
                                   OH                                     
                     sulfonyl                                             
1428  4-pyridylethyl 3,5-dimethyl- OH                                     
                     isoxazolylsulfonyl                                   
1429  4-pyridylethyl 3,5-dimethyl- OMe                                    
                     isoxazolylsulfonyl                                   
1430  4-pyridylethyl 2,4-dimethyl- OH                                     
                     thiazolylsulfonyl                                    
1431  4-pyridylethyl 2,4-dimethyl- OMe                                    
                     thiazolylsulfonyl                                    
1432  4-pyridylethyl benzylsulfonyl                                       
                                   OH                                     
1433  4-pyridylethyl styrylsulfonyl                                       
                                   OH                                     
1434  4-pyridylethyl styrylsulfonyl                                       
                                   OMe                                    
1435  4-pyridylethyl 2-benzothiophene-                                    
                                   OH                                     
                     sulfonyl                                             
1436  3-pyridylethyl n-benzyloxycarbonyl                                  
                                   OMe                                    
1437  3-pyridylethyl n-benzyloxycarbonyl                                  
                                   OH                                     
1438  3-pyridylethyl n-butyloxyoxycarbonyl                                
                                   OMe                                    
1439  3-pyridylethyl n-butyloxyoxycarbonyl                                
                                   OH                                     
1440  3-pyridylethyl 2-methylphenyl-                                      
                                   OH                                     
                     sulfonyl                                             
1441  3-pyridylethyl 2-methylphenyl-                                      
                                   OMe                                    
                     sulfonyl                                             
1442  3-pyridylethyl 2-            OH                                     
                     bromophenylsulfonyl                                  
1443  3-pyridylethyl 2-            OMe                                    
                     bromophenylsulfonyl                                  
1444  3-pyridylethyl 3-methylphenyl-                                      
                                   OH                                     
                     sulfonyl                                             
1445  3-pyridylethyl 3,5-dimethyl- OH                                     
                     isoxazolylsulfonyl                                   
1446  3-pyridylethyl 3,5-dimethyl- OMe                                    
                     isoxazolylsulfonyl                                   
1447  3-pyridylethyl 2,4-dimethyl- OH                                     
                     thiazolylsulfonyl                                    
1448  3-pyridylethyl 2,4-dimethyl- OMe                                    
                     thiazolylsulfonyl                                    
1449  3-pyridylethyl benzylsulfonyl                                       
                                   OH                                     
1450  3-pyridylethyl styrylsulfonyl                                       
                                   OH                                     
1451  3-pyridylethyl styrylsulfonyl                                       
                                   OMe                                    
1452  3-pyridylethyl 2-benzothiophene-                                    
                                   OH                                     
                     sulfonyl                                             
1453  2-amino-4-pyridylethyl                                              
                     n-benzyloxycarbonyl                                  
                                   OMe                                    
1454  2-amino-4-pyridylethyl                                              
                     n-benzyloxycarbonyl                                  
                                   OH                                     
1455  2-amino-4-pyridylethyl                                              
                     n-butyloxyoxycarbonyl                                
                                   OMe                                    
1456  2-amino-4-pyridylethyl                                              
                     n-butyloxyoxycarbonyl                                
                                   OH                                     
1457  2-amino-4-pyridylethyl                                              
                     2-methylphenyl-                                      
                                   OH                                     
                     sulfonyl                                             
1458  2-amino-4-pyridylethyl                                              
                     2-methylphenyl-                                      
                                   OMe                                    
                     sulfonyl                                             
1459  2-amino-4-pyridylethyl                                              
                     2-            OH                                     
                     bromophenylsulfonyl                                  
1460  2-amino-4-pyridylethyl                                              
                     2-            OMe                                    
                     bromophenylsulfonyl                                  
1461  2-amino-4-pyridylethyl                                              
                     3-methylphenyl-                                      
                                   OH                                     
                     sulfonyl                                             
1462  2-amino-4-pyridylethyl                                              
                     3,5-dimethyl- OH                                     
                     isoxazolylsulfonyl                                   
1463  2-amino-4-pyridylethyl                                              
                     3,5-dimethyl- OMe                                    
                     isoxazolylsulfonyl                                   
1464  2-amino-4-pyridylethyl                                              
                     2,4-dimethyl- OH                                     
                     thiazolylsulfonyl                                    
1465  2-amino-4-pyridylethyl                                              
                     2,4-dimethyl- OMe                                    
                     thiazolylsulfonyl                                    
1466  2-amino-4-pyridylethyl                                              
                     benzylsulfonyl                                       
                                   OH                                     
1467  2-amino-4-pyridylethyl                                              
                     benzylsulfonyl                                       
                                   OMe                                    
1468  2-amino-4-pyridylethyl                                              
                     styrylsulfonyl                                       
                                   OH                                     
1469  2-amino-4-pyridylethyl                                              
                     styrylsulfonyl                                       
                                   OMe                                    
1470  2-amino-4-pyridylethyl                                              
                     2-benzothiophene-                                    
                                   OH                                     
                     sulfonyl                                             
1471  6-amino-3-pyridylethyl                                              
                     n-benzyloxycarbonyl                                  
                                   OMe                                    
1472  6-amino-3-pyridylethyl                                              
                     n-benzyloxycarbonyl                                  
                                   OH                                     
1473  6-amino-3-pyridylethyl                                              
                     n-butyloxyoxycarbonyl                                
                                   OMe                                    
1474  6-amino-3-pyridylethyl                                              
                     n-butyloxyoxycarbonyl                                
                                   OH                                     
1475  6-amino-3-pyridylethyl                                              
                     2-methylphenyl-                                      
                                   OH                                     
                     sulfonyl                                             
1476  6-amino-3-pyridylethyl                                              
                     2-methylphenyl-                                      
                                   OMe                                    
                     sulfonyl                                             
1477  6-amino-3-pyridylethyl                                              
                     2-            OH                                     
                     bromophenylsulfonyl                                  
1478  6-amino-3-pyridylethyl                                              
                     2-            OMe                                    
                     bromophenylsulfonyl                                  
1479  6-amino-3-pyridylethyl                                              
                     3-methylphenyl-                                      
                                   OH                                     
                     sulfonyl                                             
1480  6-amino-3-pyridylethyl                                              
                     3,5-dimethyl- OH                                     
                     isoxazolylsulfonyl                                   
1481  6-amino-3-pyridylethyl                                              
                     3,5-dimethyl- OMe                                    
                     isoxazolylsulfonyl                                   
1482  6-amino-3-pyridylethyl                                              
                     2,4-dimethyl- OH                                     
                     thiazolylsulfonyl                                    
1483  6-amino-3-pyridylethyl                                              
                     2,4-dimethyl- OMe                                    
                     thiazolylsulfonyl                                    
1484  6-amino-3-pyridylethyl                                              
                     benzylsulfonyl                                       
                                   OH                                     
1485  6-amino-3-pyridylethyl                                              
                     benzylsulfonyl                                       
                                   OMe                                    
1486  6-amino-3-pyridylethyl                                              
                     styrylsulfonyl                                       
                                   OH                                     
1487  6-amino-3-pyridylethyl                                              
                     styrylsulfonyl                                       
                                   OMe                                    
1488  6-amino-4-pyridylethyl                                              
                     2-benzothiophene-                                    
                                   OH                                     
                     sulfonyl                                             
1489  2-amidino-4-pyridylethyl                                            
                     n-benzyloxycarbonyl                                  
                                   OMe                                    
1490  2-amidino-4-pyridylethyl                                            
                     n-benzyloxycarbonyl                                  
                                   OH                                     
1491  2-amidino-4-pyridylethyl                                            
                     n-butyloxyoxycarbonyl                                
                                   OMe                                    
1492  2-amidino-4-pyridylethyl                                            
                     n-butyloxyoxycarbonyl                                
                                   OH                                     
1493  2-amidino-4-pyridylethyl                                            
                     2-methylphenyl-                                      
                                   OH                                     
                     sulfonyl                                             
1494  2-amidino-4-pyridylethyl                                            
                     2-methylphenyl-                                      
                                   OMe                                    
                     sulfonyl                                             
1495  2-amidino-4-pyridylethyl                                            
                     2-            OH                                     
                     bromophenylsulfonyl                                  
1496  2-amidino-4-pyridylethyl                                            
                     2-            OMe                                    
                     bromophenylsulfonyl                                  
1497  2-amidino-4-pyridylethyl                                            
                     3-methylphenyl-                                      
                                   OH                                     
                     sulfonyl                                             
1498  2-amidino-4-pyridylethyl                                            
                     3,5-dimethyl- OH                                     
                     isoxazolylsulfonyl                                   
1499  2-amidino-4-pyridylethyl                                            
                     3,5-dimethyl- OMe                                    
                     isoxazolylsulfonyl                                   
1500  2-amidino-4-pyridylethyl                                            
                     2,4-dimethyl- OH                                     
                     thiazolylsulfonyl                                    
1501  2-amidino-4-pyridylethyl                                            
                     2,4-dimethyl- OMe                                    
                     thiazolylsulfonyl                                    
1502  2-amidino-4-pyridylethyl                                            
                     benzylsulfonyl                                       
                                   OH                                     
1503  2-amidino-4-pyridylethyl                                            
                     benzylsulfonyl                                       
                                   OMe                                    
1504  2-amidino-4-pyridylethyl                                            
                     styrylsulfonyl                                       
                                   OH                                     
1505  2-amidino-4-pyridylethyl                                            
                     styrylsulfonyl                                       
                                   OMe                                    
1506  2-amidino-4-pyridylethyl                                            
                     2-benzothiophene-                                    
                                   OH                                     
                     sulfonyl                                             
1507  6-amidino-3-pyridylethyl                                            
                     n-benzyloxycarbonyl                                  
                                   OMe                                    
1508  6-amidino-3-pyridylethyl                                            
                     n-benzyloxycarbonyl                                  
                                   OH                                     
1509  6-amidino-3-pyridylethyl                                            
                     n-butyloxyoxycarbonyl                                
                                   OMe                                    
1510  6-amidino-3-pyridylethyl                                            
                     n-butyloxyoxycarbonyl                                
                                   OH                                     
1511  6-amidino-3-pyridylethyl                                            
                     2-methylphenyl-                                      
                                   OH                                     
                     sulfonyl                                             
1512  6-amidino-3-pyridylethyl                                            
                     2-methylphenyl-                                      
                                   OMe                                    
                     sulfonyl                                             
1513  6-amidino-3-pyridylethyl                                            
                     2-            OH                                     
                     bromophenylsulfonyl                                  
1514  6-amidino-3-pyridylethyl                                            
                     2-            OMe                                    
                     bromophenylsulfonyl                                  
1515  6-amidino-3-pyridylethyl                                            
                     3-methylphenyl-                                      
                                   OH                                     
                     sulfonyl                                             
1516  6-amidino-3-pyridylethyl                                            
                     3,5-dimethyl- OH                                     
                     isoxazolylsulfonyl                                   
1517  6-amidino-3-pyridylethyl                                            
                     3,5-dimethyl- OMe                                    
                     isoxazolylsulfonyl                                   
1518  6-amidino-3-pyridylethyl                                            
                     2,4-dimethyl- OH                                     
                     thiazolylsulfonyl                                    
1519  6-amidino-3-pyridylethyl                                            
                     2,4-dimethyl- OMe                                    
                     thiazolylsulfonyl                                    
1520  6-amidino-3-pyridylethyl                                            
                     benzylsulfonyl                                       
                                   OH                                     
1521  6-amidino-3-pyridylethyl                                            
                     benzylsulfonyl                                       
                                   Me                                     
1522  6-amidino-3-pyridylethyl                                            
                     styrylsulfonyl                                       
                                   OH                                     
1523  6-amidino-3-pyridylethyl                                            
                     styrylsulfonyl                                       
                                   OMe                                    
1524  6-amidino-3-pyridylethyl                                            
                     2-benzothiophene-                                    
                                   OH                                     
                     sulfonyl                                             
1525  guanidinoethyl benzyloxycarbonyl                                    
                                   OH   421                               
______________________________________                                    

              TABLE 8                                                     
______________________________________                                    
 ##STR360##                                                               
Ex.                                        MS                             
No.  R.sup.1 --V p.sup.1                                                  
                       p.sup.2                                            
                           R.sup.16   Y    M +  H                         
______________________________________                                    
1540 4-amidinophenyl                                                      
                 2     1   n-butyloxycarbonyl                             
                                      OH   446                            
1541 4-amidinophenyl                                                      
                 2     1   3-methylphenyl-                                
                                      OH   448                            
                           sulfonyl                                       
1542 4-amidinophenyl                                                      
                 1     1   benzyloxycarbonyl                              
                                      OMe                                 
1543 4-amidinophenyl                                                      
                 1     1   (2-methylphenyl)-                              
                                      OH                                  
                           methoxycarbonyl                                
1544 4-amidinophenyl                                                      
                 1     1   (3-methylphenyl)-                              
                                      OH                                  
                           methoxycarbonyl                                
1545 4-amidinophenyl                                                      
                 1     2   i-butyloxycarbonyl                             
                                      OMe                                 
1546 4-amidinophenyl                                                      
                 1     2   4-methylphenyl-                                
                                      OH                                  
                           sulfonyl                                       
1547 4-amidinophenyl                                                      
                 1     2   2-methylphenyl-                                
                                      OH                                  
                           sulfonyl                                       
1548 4-amidinophenyl                                                      
                 2     1   3,5-dimethylpyra-                              
                                      OH                                  
                           zoylsulfonyl                                   
1549 4-amidinophenyl                                                      
                 2     1   3,5-dimethylisox-                              
                                      OH                                  
                           azoylsulfonyl                                  
1550 4-amidinophenyl                                                      
                 2     1   i-butylamino-                                  
                                      OH                                  
                           sulfonyl                                       
1551 4-amidinophenyl                                                      
                 2     1   2-bromophenyl-                                 
                                      OH                                  
                           sulfonyl                                       
1552 4-piperidinylethyl                                                   
                 1     1   n-propyloxy-                                   
                                      OMe                                 
                           carbonyl                                       
1553 4-piperidinylethyl                                                   
                 1     2   n-butylsulfonyl                                
                                      OH                                  
1554 4-piperidinylethyl                                                   
                 1     2   (3-bromophenyl)-                               
                                      OH                                  
                           methylsulfony1                                 
1555 4-piperidinylethyl                                                   
                 2     1   (3-methylphenyl)-                              
                                      OMe                                 
                           methoxycarbonyl                                
1556 4-piperidinylethyl                                                   
                 2     1   2-phenylethoxy-                                
                                      OH                                  
                           carbonyl                                       
1557 4-(N-benzylamid-                                                     
                 1     1   n-butyloxycarbonyl                             
                                      OH                                  
     ino)phenyl                                                           
1558 4-[N-(2-methyl-                                                      
                 1     1   3-methylphenyl-                                
                                      OH                                  
     phenyl)-methyl-       sulfonyl                                       
     amidino]phenyl                                                       
1559 4-[N-(2-bromo-                                                       
                 1     2   2-bromophenyl-                                 
                                      OH                                  
     phenyl)-methyl-       sulfonyl                                       
     amidino]phenyl                                                       
1560 4-(N-butyl- 2     1   3,5-dimethylpyra-                              
                                      OH                                  
     amidino)phenyl        zoylsulfonyl                                   
1561 4-[N-(2-    2     1   3-methylphenyl-                                
                                      OH                                  
     methoxyphenyl)-       sulfonyl                                       
     methyl-                                                              
     amidino]phenyl                                                       
1562 4-[N-(3-[trifluoro-                                                  
                 2     1   2,5-dimethyl-                                  
                                      OH                                  
     methyl]phen-          thiazolylsulfonyl                              
     yl)methyl-                                                           
     amidino]phenyl                                                       
1563 4-amidino-2-                                                         
                 1     1   3-methylphenyl-                                
                                      OH                                  
     fluorophenyl          sulfonyl                                       
1564 4-amidino-2-                                                         
                 1     2   i-butylamino-                                  
     fluorophenyl          sulfonyl                                       
1565 4-amidino-2-                                                         
                 2     1   3,5-dimethylisoxa-                             
                                      OH                                  
     fluorophenyl          zoylsulfonyl                                   
1566 5-amidino-2-                                                         
                 1     1   n-butyloxycarbonyl                             
                                      OMe                                 
     pyridyl                                                              
1567 5-amidino-2-                                                         
                 1     2   2-methylphenyl-                                
                                      OH                                  
     pyridyl               sulfonyl                                       
1568 5-amidino-2-                                                         
                 1     2   3-methylphenyl-                                
                                      OMe                                 
     pyridyl               sulfonyl                                       
1569 5-amidino-2-                                                         
                 2     1   n-butylsulfonyl                                
                                      OH                                  
     pyridyl                                                              
1570 5-amidino-2-                                                         
                 2     1   3,5-dimethylisoxa-                             
                                      OH                                  
     pyridyl               zoylsulfonyl                                   
1571 2-amidino-5-                                                         
                 1     1   2-bromophenyl-                                 
                                      OH                                  
     pyridyl               sulfonyl                                       
1572 2-amidino-5-                                                         
                 1     1   2-(trifluoromethyl)-                           
                                      OMe                                 
     pyridyl               phenylsulfonyl                                 
1573 2-amidino-5-                                                         
                 1     2   n-propylamino-                                 
                                      OMe                                 
     pyridyl               carbonyl                                       
1574 2-amidino-5-                                                         
                 1     2   4-methylphenyl-                                
                                      OH                                  
     pyridyl               sulfonyl                                       
1575 2-amidino-5-                                                         
                 2     1   2-fluorophenyl-                                
                                      OH                                  
     pyridyl               sulfonyl                                       
______________________________________                                    

                                  TABLE 9                                 
__________________________________________________________________________
 ##STR361##                                                               
Example                             MS                                    
Number                                                                    
     R.sup.1 -V  R.sup.16       Y   (M + H).sup.+                         
__________________________________________________________________________
1585 4-piperidinylethyl                                                   
                 n-butyloxycarbonyl                                       
                                OMe 441                                   
1585A                                                                     
     4-piperidinylmethyl                                                  
                 n-butyloxycarbonyl                                       
                                OH  427                                   
1586 4-piperidinylethyl                                                   
                 benzyloxycarbonyl                                        
                                OMe                                       
1587 4-piperidinylethyl                                                   
                 n-propyloxycarbonyl                                      
                                OMe                                       
1588 4-piperidinylethyl                                                   
                 isobutyloxycarbonyl                                      
                                OMe                                       
1589 4-piperidinylethyl                                                   
                 2-methylphenylsulfonyl                                   
                                OMe                                       
1590 4-piperidinylethyl                                                   
                 3-methylphenylsulfonyl                                   
                                OMe                                       
1591 4-piperidinylethyl                                                   
                 4-methylphenylsulfonyl                                   
                                OMe                                       
1592 4-piperidinylethyl                                                   
                 2-bromophenylsulfonyl                                    
                                OMe                                       
1593 4-piperidinylethyl                                                   
                 3-bromophenylsulfonyl                                    
                                OMe                                       
1594 4-piperidinylethyl                                                   
                 2-methoxyphenyl-                                         
                                OMe                                       
                 sulfonyl                                                 
1595 4-piperidinylethyl                                                   
                 3-methoxyphenyl-                                         
                                OMe                                       
                 sulfonyl                                                 
1596 4-piperidinylethyl                                                   
                 3-trifluoromethyl-                                       
                                OMe                                       
                 phenylsulfonyl                                           
1597 4-piperidinylethyl                                                   
                 n-propylsulfonyl                                         
                                OMe                                       
1598 4-piperidinylethyl                                                   
                 n-butylsulfonyl                                          
                                OMe                                       
1599 4-piperidinylethyl                                                   
                 isopropylsulfonyl                                        
                                OMe                                       
1600 4-piperidinylethyl                                                   
                 isobutylsulfonyl                                         
                                OMe                                       
1601 4-piperidinylethyl                                                   
                 3,5-dimethyl-  OMe                                       
                 isoxazolylsulfonyl                                       
1602 4-piperidinylethyl                                                   
                 2,4-dimethyl-  OMe                                       
                 thiazolylsulfonyl                                        
1603 4-piperidinylpropyl                                                  
                 n-butyloxycarbonyl                                       
                                OMe 455                                   
1604 4-piperidinylpropyl                                                  
                 n-propyloxycarbonyl                                      
                                OMe                                       
1605 4-piperidinylpropyl                                                  
                 benzyloxycarbonyl                                        
                                OMe                                       
1606 4-piperidinylpropyl                                                  
                 isobutyloxycarbonyl                                      
                                OMe                                       
1607 4-piperidinylpropyl                                                  
                 2-methylphenyl-                                          
                                OMe                                       
                 sulfonyl                                                 
1608 4-piperidinylpropyl                                                  
                 3-methylphenyl-                                          
                                OMe                                       
                 sulfonyl                                                 
1609 4-piperidinylpropyl                                                  
                 4-methylphenyl-                                          
                                OMe 509                                   
                 sulfonyl                                                 
1610 4-piperidinylpropyl                                                  
                 2-bromophenylsulfonyl                                    
                                OMe                                       
1611 4-piperidinylpropyl                                                  
                 n-butylsulfonyl                                          
                                OMe                                       
1612 4-piperidinylpropyl                                                  
                 isobutylsulfonyl                                         
                                OMe                                       
1613 4-piperidinylpropyl                                                  
                 3,5-dimethyl-  OMe                                       
                 isoxazolylsulfonyl                                       
1614 4-piperidinylpropyl                                                  
                 2,4-dimethyl-  OMe                                       
                 thiazoylsulfonyl                                         
1615 4-piperidinylethyl                                                   
                 n-butyloxycarbonyl                                       
                                OH                                        
1616 4-piperidinylethyl                                                   
                 n-propyloxycarbonyl                                      
                                OH                                        
1617 4-piperidinylethyl                                                   
                 benyloxycarbonyl                                         
                                OH                                        
1618 4-piperidinylethyl                                                   
                 isobutyloxycarbonyl                                      
                                OH                                        
1619 4-piperidinylethyl                                                   
                 2-methylphenyl-                                          
                                OH  481                                   
                 sulfonyl                                                 
1620 4-piperidinylethyl                                                   
                 3-methylphenyl-                                          
                                OH  481                                   
                 sulfonyl                                                 
1621 4-piperidinylethyl                                                   
                 4-methylphenyl-                                          
                                OH  481                                   
                 sulfonyl                                                 
1622 4-piperidinylethyl                                                   
                 2-bromophenylsulfonyl                                    
                                OH  545                                   
1623 4-piperidinylethyl                                                   
                 3,5-dimethyl-  OH  486                                   
                 isoxazolylsulfonyl                                       
1624 4-piperidinylethyl                                                   
                 2,4-dimethyl-  OH  502                                   
                 thiazolylsulfonyl                                        
1625 4-piperidinylethyl                                                   
                 n-butylsulfonyl                                          
                                OH  447                                   
1626 4-piperidinylethyl                                                   
                 isobutylsulfonyl                                         
                                OH                                        
1627 4-piperidinylpropyl                                                  
                 n-butyloxycarbonyl                                       
                                OH  441                                   
1628 4-piperidinylpropyl                                                  
                 n-propyloxycarbonyl                                      
                                OH                                        
1629 4-piperidinylpropyl                                                  
                 isobutyloxycarbonyl                                      
                                OH                                        
1630 4-piperidinylpropyl                                                  
                 2-methylphenyl-                                          
                                OH                                        
                 carbonyl                                                 
1631 4-piperidinylpropyl                                                  
                 4-methylphenyl-                                          
                                OH  495                                   
                 carbonyl                                                 
1632 4-piperidinylpropyl                                                  
                 2-bromophenyl-carbonyl                                   
                                OH                                        
1633 4-piperidinylpropyl                                                  
                 3,5-dimethyl-  OH                                        
                 isoxazolylsulfonyl                                       
1634 4-piperidinylpropyl                                                  
                 n-butylsulfonyl                                          
                                OH                                        
1635 4-piperidinylpropyl                                                  
                 isobutylsulfonyl                                         
                                OH                                        
1636 4-amidinopiperidinyl                                                 
                 n-butyloxycarbonyl                                       
                                OMe                                       
1637 4-amidinopiperidinyl                                                 
                 isobutyloxycarbonyl                                      
                                OMe                                       
1638 4-amidinopiperidinyl                                                 
                 n-propyloxycarbonyl                                      
                                OMe                                       
1639 4-amidinopiperidinyl                                                 
                 benzyloxycarbonyl                                        
                                OMe                                       
1640 4-amidinopiperidinyl                                                 
                 n-butylsulfonyl                                          
                                OMe                                       
1641 4-amidinopiperidinyl                                                 
                 isobutylsulfonyl                                         
                                OMe                                       
1642 4-amidinopiperidinyl                                                 
                 n-propylsulfonyl                                         
                                OMe                                       
1643 4-amidinopiperidinyl                                                 
                 2-methylphenyl-                                          
                                OMe                                       
                 sulfonyl                                                 
1644 4-amidinopiperidinyl                                                 
                 4-methylphenyl-                                          
                                OMe                                       
                 sulfonyl                                                 
1645 4-amidinopiperidinyl                                                 
                 benzylsulfonyl OMe                                       
1646 4-amidinopiperidinyl                                                 
                 3,5-dimethyl-  OMe                                       
                 isoxazolylsulfonyl                                       
1647 4-amidinopiperidinyl                                                 
                 2,4-dimethyl-  OMe                                       
                 thiazolylsulfonyl                                        
1648 4-amidinopiperidinyl                                                 
                 4-methylphenyl-                                          
                                OH                                        
                 sulfonyl                                                 
1649 4-amidinopiperidinyl                                                 
                 n-butyloxycarbonyl                                       
                                OH                                        
1650 4-amidinopiperidinyl                                                 
                 isobutyloxycarbonyl                                      
                                OH                                        
1651 4-amidinopiperidinyl                                                 
                 n-propyloxycarbonyl                                      
                                OH                                        
1652 4-amidinopiperidinyl                                                 
                 benzyloxycarbonyl                                        
                                OH                                        
1653 4-amidinopiperidinyl                                                 
                 n-butylsulfonyl                                          
                                OH                                        
1654 4-amidinopiperidinyl                                                 
                 isobutylsulfonyl                                         
                                OH                                        
1655 4-amidinopiperidinyl                                                 
                 2-methylphenyl-                                          
                                OH                                        
                 sulfonyl                                                 
1656 4-amidinopiperidinyl                                                 
                 3-methylphenyl-                                          
                                OH  495                                   
                 sulfonyl                                                 
1657 4-amidinopiperidinyl                                                 
                 4-methylphenyl-                                          
                                OH  495                                   
                 sulfonyl                                                 
1658 4-amidinopiperidinyl                                                 
                 2-bromophenylsulfonyl                                    
                                OH                                        
1659 4-amidinopiperidinyl                                                 
                 3-bromophenylsulfonyl                                    
                                OH                                        
1660 4-amidinopiperidinyl                                                 
                 3,5-dimethyl-  OH                                        
                 isoxazolylsulfonyl                                       
1661 4-amidinopiperidinyl                                                 
                 2,4-dimethyl-  OH                                        
                 thiazolylsulfonyl                                        
1662 4-amidino-  n-butyloxycarbonyl                                       
                                OMe 427                                   
     piperidinylmethyl                                                    
1663 4-amidino-  n-propyloxycarbonyl                                      
                                OMe                                       
     piperidinylmethyl                                                    
1664 4-amidino-  benzyloxycarbonyl                                        
                                OMe                                       
     piperidinylmethyl                                                    
1665 4-amidino-  n-butylsulfonyl                                          
                                OMe                                       
     piperidinylmethyl                                                    
1666 4-amidino-  n-propylsulfonyl                                         
                                OMe                                       
     piperidinylmethyl                                                    
1667 4-amidino-  2-methylphenyl-                                          
                                OMe                                       
     piperidinylmethyl                                                    
                 sulfonyl                                                 
1668 4-amidino-  3-methylphenyl-                                          
                                OMe                                       
     piperidinylmethyl                                                    
                 sulfonyl                                                 
1669 4-amidino-  4-methylphenyl-                                          
                                OMe                                       
     piperidinylmethyl                                                    
                 sulfonyl                                                 
1670 4-amidino-  2-bromophenylsulfonyl                                    
                                OMe                                       
     piperidinylmethyl                                                    
1671 4-amidino-  3-bromophenylsulfonyl                                    
                                OMe                                       
     piperidinylmethyl                                                    
1672 4-amidino-  3,5-dimethyl-  OMe                                       
     piperidinylmethyl                                                    
                 isoxazolylsulfonyl                                       
1673 4-amidino-  4-methylphenyl-                                          
                                OH  509                                   
     piperidinylmethyl                                                    
                 sulfonyl                                                 
1674 4-amidino-  n-butyloxycarbonyl                                       
                                OH                                        
     piperidinylmethyl                                                    
1675 4-amidino-  n-propyloxycarbonyl                                      
                                OH                                        
     piperidinylmethyl                                                    
1676 4-amidino-  benzyloxycarbonyl                                        
                                OH                                        
     piperidinylmethyl                                                    
1677 4-amidino-  n-butylsulfonyl                                          
                                OH                                        
     piperidinylmethyl                                                    
1678 4-amidino-  2-methylphenyl-                                          
                                OH                                        
     piperidinylmethyl                                                    
                 sulfonyl                                                 
1679 4-amidino-  3-methylphenyl-                                          
                                OH                                        
     piperidinylmethyl                                                    
                 sulfonyl                                                 
1680 4-amidino-  2-bromophenyl-sulfonyl                                   
                                OH                                        
     piperidinylmethyl                                                    
1681 4-amidino-  3-bromophenyl-sulfonyl                                   
                                OH                                        
     piperidinylmethyl                                                    
1682 4-amidino-  3,5-dimethyl-  OH                                        
     piperidinylmethyl                                                    
                 isoxazolylsulfonyl                                       
1683 4-quinuclidinylethyl                                                 
                 n-butyloxycarbonyl                                       
                                OH                                        
1684 4-quinuclidinylethyl                                                 
                 n-propyloxycarbonyl                                      
                                OH                                        
1685 4-quinuclidinylethyl                                                 
                 benzyloxycarbonyl                                        
                                OH                                        
1686 4-quinuclidinylethyl                                                 
                 n-butylsulfonyl                                          
                                OH                                        
1687 4-quinuclidinylethyl                                                 
                 2-methylphenyl-                                          
                                OH                                        
                 sulfonyl                                                 
1688 4-quinuclidinylethyl                                                 
                 4-methylphenyl-                                          
                                OH                                        
                 sulfonyl                                                 
1689 4-quinuclidinylethyl                                                 
                 2-bromophenylsulfonyl                                    
                                OH                                        
1690 4-quinuclidinylethyl                                                 
                 3-bromophenylsulfonyl                                    
                                OH                                        
1691 4-quinuclidinylethyl                                                 
                 3,5-dimethyl-  OH                                        
                 isoxazolylsulfonyl                                       
1692 guanidinopropyl                                                      
                 n-butyloxycarbonyl                                       
                                OMe                                       
1693 guanidinopropyl                                                      
                 n-propyloxycarbonyl                                      
                                OMe                                       
1694 guanidinopropyl                                                      
                 benzyloxycarbonyl                                        
                                OH  449                                   
1695 guanidinopropyl                                                      
                 n-butylsulfonyl                                          
                                OMe                                       
1696 guanidinopropyl                                                      
                 2-methylphenyl-                                          
                                OMe                                       
                 sulfonyl                                                 
1697 guanidinopropyl                                                      
                 3-methylphenyl-                                          
                                OMe                                       
                 sulfonyl                                                 
1698 guanidinopropyl                                                      
                 2-bromophenylsulfonyl                                    
                                OMe                                       
1699 guanidinopropyl                                                      
                 3-bromophenylsulfonyl                                    
                                OMe                                       
1700 guanidinopropyl                                                      
                 3,5-dimethyl-  OMe                                       
                 isoxazolylsulfonyl                                       
1701 guanidinopropyl                                                      
                 benzylsulfonyl OMe                                       
1702 guanidinopropyl                                                      
                 styrylsulfonyl OMe                                       
1703 guanidinopropyl                                                      
                 2-benzothiophene-                                        
                                OMe                                       
                 sulfonyl                                                 
1704 guanidinopropyl                                                      
                 n-butyloxycarbonyl                                       
                                OH  529                                   
1705 guanidinopropyl                                                      
                 n-propyloxycarbonyl                                      
                                OH                                        
1706 guanidinopropyl                                                      
                 benzyloxycarbonyl                                        
                                OH                                        
1707 guanidinopropyl                                                      
                 n-butylsulfonyl                                          
                                OH                                        
1708 guanidinopropyl                                                      
                 2-methylphenyl-                                          
                                OH                                        
                 sulfonyl                                                 
1709 guanidinopropyl                                                      
                 3-methylphenyl-                                          
                                OH                                        
                 sulfonyl                                                 
1710 guanidinopropyl                                                      
                 4-methylphenyl-                                          
                                OH                                        
                 sulfonyl                                                 
1711 guanidinopropyl                                                      
                 2-bromophenylsulfonyl                                    
                                OH                                        
1712 guanidinopropyl                                                      
                 3-bromophenylsulfonyl                                    
                                OH                                        
1713 guanidinopropyl                                                      
                 3,5-dimethyl-  OH                                        
                 isoxazolylsulfonyl                                       
1714 guanidinopropyl                                                      
                 2,4-dimethyl-  OH                                        
                 thiazolylsulfonyl                                        
1715 guanidinopropyl                                                      
                 benzylsulfonyl OH                                        
1716 guanidinopropyl                                                      
                 styrylsulfonyl OH                                        
1717 guanidinopropyl                                                      
                 2-benzothiophene-                                        
                                OH                                        
                 sulfonyl                                                 
1718 guanidinobutyl                                                       
                 n-butyloxycarbonyl                                       
                                OH                                        
1719 guanidinobutyl                                                       
                 n-butylsulfonyl                                          
                                OH                                        
1720 guanidinobutyl                                                       
                 phenylsulfonyl OH                                        
1721 guanidinobutyl                                                       
                 2-methylphenyl-                                          
                                OH                                        
                 sulfonyl                                                 
1722 guanidinobutyl                                                       
                 4-methylphenyl-                                          
                                OH                                        
                 sulfonyl                                                 
1723 guanidinobutyl                                                       
                 2-bromophenylsulfonyl                                    
                                OH                                        
1724 guanidinobutyl                                                       
                 3,5-dimethyl-  OH                                        
                 isoxazolylsulfonyl                                       
1725 guanidinobutyl                                                       
                 2,4-dimethyl-  OH                                        
                 thiazolylsulfonyl                                        
1726 guanidinobutyl                                                       
                 benzylsulfonyl OH                                        
1727 guanidinobutyl                                                       
                 styrylsulfonyl OH                                        
1728 guanidinobutyl                                                       
                 3-fluorophenyl-                                          
                                OH                                        
                 sulfonyl                                                 
1729 guanidinobutyl                                                       
                 n-butyloxycarbonyl                                       
                                OMe                                       
1730 guanidinobutyl                                                       
                 n-butylsulfonyl                                          
                                OMe                                       
1731 guanidinobutyl                                                       
                 benzyloxycarbonyl                                        
                                OH  463                                   
1732 guanidinobutyl                                                       
                 phenylsulfonyl OMe                                       
1733 guanidinobutyl                                                       
                 2-methylphenyl-                                          
                                OMe                                       
                 sulfonyl                                                 
1734 guanidinobutyl                                                       
                 2-bromophenylsulfonyl                                    
                                OMe                                       
1735 guanidinobutyl                                                       
                 3-bromophenylsulfonyl                                    
                                OMe                                       
1736 guanidinobutyl                                                       
                 3,5-dimethyl-  OMe                                       
                 isoxazolyl sufonyl                                       
1737 guanidinobutyl                                                       
                 benzylsulfonyl OMe                                       
1738 guanidinobutyl                                                       
                 n-butyloxycarbonyl                                       
                                OH                                        
1739 guanidinobutyl                                                       
                 isobutyloxycarbonyl                                      
                                OH                                        
1740 guanidinobutyl                                                       
                 n-propyloxycarbonyl                                      
                                OH                                        
1741 guanidinobutyl                                                       
                 phenylsulfonyl OH                                        
1742 guanidinobutyl                                                       
                 n-butylsulfonyl                                          
                                OH                                        
1743 guanidinobutyl                                                       
                 2-methylphenyl-                                          
                                OH                                        
                 sulfonyl                                                 
1744 guanidinobutyl                                                       
                 3-methylphenyl-                                          
                                OH                                        
                 sulfonyl                                                 
1745 guanidinobutyl                                                       
                 4-methylphenyl-                                          
                                OH                                        
                 sulfonyl                                                 
1746 guanidinobutyl                                                       
                 2-bromophenylsulfonyl                                    
                                OH                                        
1747 4-piperidinylmethyl-                                                 
                 n-butyloxycarbonyl                                       
                                OH                                        
     aminocarbonyl                                                        
1748 4-piperidinylmethyl-                                                 
                 n-butyloxycarbonyl                                       
                                OMe                                       
     amino-carbonyl                                                       
1749 4-piperidinylmethyl-                                                 
                 benzyloxycarbonyl                                        
                                OH                                        
     amino-carbonyl                                                       
1750 4-piperidinylmethyl-                                                 
                 benzyloxycarbonyl                                        
                                OMe                                       
     amino-carbonyl                                                       
1751 4-piperidinylmethyl-                                                 
                 n-butylsulfonyl                                          
                                OH                                        
     amino-carbonyl                                                       
1752 4-piperidinylmethyl-                                                 
                 n-butylsulfonyl                                          
                                OMe                                       
     amino-carbonyl                                                       
1753 4-piperidinylmethyl-                                                 
                 2-methylphenyl-                                          
                                OH                                        
     amino-carbonyl                                                       
                 sulfonyl                                                 
1754 4-piperidinylmethyl-                                                 
                 2-methylphenyl-                                          
                                OMe                                       
     amino-carbonyl                                                       
                 sulfonyl                                                 
1755 4-piperidinylmethyl-                                                 
                 3-methylphenyl-                                          
                                OH                                        
     amino-carbonyl                                                       
                 sulfonyl                                                 
1756 4-piperidinylmethyl-                                                 
                 4-methylphenyl-                                          
                                OH  510                                   
     amino-carbonyl                                                       
                 sulfonyl                                                 
1757 4-piperidinylmethyl-                                                 
                 3-methylphenyl-                                          
                                OMe                                       
     amino-carbonyl                                                       
                 sulfonyl                                                 
1758 4-piperidinylmethyl-                                                 
                 3,5-dimethyl-  OH                                        
     amino-carbonyl                                                       
                 isoxazolylsulfonyl                                       
1759 4-piperidinylmethyl-                                                 
                 3,5-dimethyl-  OMe                                       
     amino-carbonyl                                                       
                 isoxazolylsulfonyl                                       
1760 N-(4-piperidinyl-                                                    
                 n-butyloxycarbonyl                                       
                                OH                                        
     methyl)-N-methyl-                                                    
     aminocarbonyl                                                        
1761 N-(4-piperidinyl-                                                    
                 n-butyloxycarbonyl                                       
                                OMe                                       
     methyl)-N-methyl-                                                    
     aminocarbonyl                                                        
1762 N-(4-piperidinyl-                                                    
                 benzyloxycarbonyl                                        
                                OH                                        
     methyl)-N-methyl-                                                    
     aminocarbonyl                                                        
1763 N-(4-piperidinyl-                                                    
                 benzyloxycarbonyl                                        
                                OMe                                       
     methyl)-N-methyl-                                                    
     aminocarbonyl                                                        
1764 N-(4-piperidinyl-                                                    
                 n-butylsulfonyl                                          
                                OH                                        
     methyl)-N-methyl-                                                    
     aminocarbonyl                                                        
1765 N-(4-piperidinyl-                                                    
                 n-butylsulfonyl                                          
                                OMe                                       
     methyl)-N-                                                           
     methylaminocarbonyl                                                  
1766 N-(4-piperidinyl-                                                    
                 2-methylphenyl-                                          
                                OH                                        
     methyl)-N-methyl-                                                    
                 sulfonyl                                                 
     aminocarbonyl                                                        
1767 N-(4-piperidinyl-                                                    
                 2-methylphenyl-                                          
                                OMe                                       
     methyl)-N-methyl-                                                    
                 sulfonyl                                                 
     aminocarbonyl                                                        
1768 N-(4-piperidinyl-                                                    
                 3-methylphenyl-                                          
                                OH                                        
     methyl)-N-methyl-                                                    
                 sulfonyl                                                 
     aminocarbonyl                                                        
1769 N-(4-piperidinyl-                                                    
                 4-methylphenyl-                                          
                                OH  524                                   
     methyl)-N-methyl-                                                    
                 sulfonyl                                                 
     aminocarbonyl                                                        
1770 N-(4-piperidinyl-                                                    
                 3-methylphenyl-                                          
                                OMe                                       
     methyl)-N-methyl-                                                    
                 sulfonyl                                                 
     aminocarbonyl                                                        
1771 N-(4-piperidinyl-                                                    
                 3,5-dimethyl-  OH                                        
     methyl)-N-methyl-                                                    
                 isoxazolylsulfonyl                                       
     aminocarbonyl                                                        
1772 N-(4-piperidinyl-                                                    
                 3,5-dimethyl-  OMe                                       
     methyl)-N-methyl-                                                    
                 isoxazolylsulfonyl                                       
     aminocarbonyl                                                        
1773 4-piperidinyl-                                                       
                 n-butyloxycarbonyl                                       
                                OH                                        
     aminocarbonyl                                                        
1774 4-piperidinyl-                                                       
                 4-methylphenyl-                                          
                                OH  496                                   
     aminocarbonyl                                                        
                 sulfonyl                                                 
1775 4-guanidinophenyl                                                    
                 2-methylphenyl-                                          
                                OH                                        
                 sulfonyl                                                 
1776 4-guanidinophenyl                                                    
                 2-methylphenyl-                                          
                                OMe                                       
                 sulfonyl                                                 
1777 4-guanidinophenyl                                                    
                 2-bromophenylsulfonyl                                    
                                OH                                        
1778 4-guanidinophenyl                                                    
                 2-bromophenylsulfonyl                                    
                                OMe                                       
1779 4-guanidinophenyl                                                    
                 3-methylphenyl-                                          
                                OH                                        
                 sulfonyl                                                 
1780 4-guanidinophenyl                                                    
                 3,5-dimethyl-  OH                                        
                 isoxazolylsulfonyl                                       
1781 4-guanidinophenyl                                                    
                 3,5-dimethyl-  OMe                                       
                 isoxazolylsulfonyl                                       
1782 4-guanidinophenyl                                                    
                 2,4-dimethyl-  OH                                        
                 thiazolylsulfonyl                                        
1783 4-guanidinophenyl                                                    
                 2,4-dimethyl-  OMe                                       
                 thiazolylsulfonyl                                        
1784 4-guanidinophenyl                                                    
                 benzylsulfonyl OH                                        
1785 4-guanidinophenyl                                                    
                 benzylsulfonyl OMe                                       
1786 4-guanidinophenyl                                                    
                 styrylsulfonyl OH                                        
1787 4-guanidinophenyl                                                    
                 styrylsulfonyl OMe                                       
1788 4-guanidinophenyl                                                    
                 2-benzothiophene-                                        
                                OH                                        
                 sulfonyl                                                 
1789 3-guanidinophenyl                                                    
                 n-butyloxycarbonyl                                       
                                OH                                        
1790 3-guanidinophenyl                                                    
                 n-butyloxycarbonyl                                       
                                OMe                                       
1791 3-guanidinophenyl                                                    
                 n-propyloxycarbonyl                                      
                                OH                                        
1792 3-guanidinophenyl                                                    
                 2-bromophenylsulfonyl                                    
                                OH                                        
1793 3-guanidinophenyl                                                    
                 2-bromophenylsulfonyl                                    
                                OMe                                       
1794 3-guanidinophenyl                                                    
                 2-methylphenyl-                                          
                                OH                                        
                 sulfonyl                                                 
1795 3-guanidinophenyl                                                    
                 4-methylphenyl-                                          
                                OH                                        
                 sulfonyl                                                 
1796 3-guanidinophenyl                                                    
                 4-methylphenyl-                                          
                                OMe                                       
                 sulfonyl                                                 
1797 3-guanidinophenyl                                                    
                 n-butylsulfonyl                                          
                                OH                                        
1798 3-guanidinophenyl                                                    
                 n-butylsulfonyl                                          
                                OMe                                       
1799 3-guanidinophenyl                                                    
                 styrylsulfonyl OH                                        
1800 3-guanidinophenyl                                                    
                 benzyloxycarbonyl                                        
                                OH                                        
1801 3-guanidinophenyl                                                    
                 benzyloxycarbonyl                                        
                                OMe                                       
1802 4-amidinophenylmethyl                                                
                 2-methylphenyl-                                          
                                OH                                        
                 sulfonyl                                                 
1803 4-amidinophenylmethyl                                                
                 2-methylphenyl-                                          
                                OMe                                       
                 sulfonyl                                                 
1804 4-amidinophenylmethyl                                                
                 phenylsulfonyl OH                                        
1805 4-amidinophenylmethyl                                                
                 phenylsulfonyl OMe                                       
1806 4-amidinophenylmethyl                                                
                 3,5-dimethyl-  OH                                        
                 isoxazolylsulfonyl                                       
1807 4-amidinophenylmethyl                                                
                 3,5-dimethyl-  OMe                                       
                 isoxazolylsulfonyl                                       
1898 4-amidinophenylmethyl                                                
                 2,4-dimethyl-  OH                                        
                 thiazolylsulfonyl                                        
1809 4-amidinophenylmethyl                                                
                 2,4-dimethyl-  OMe                                       
                 thiazolylsulfonyl                                        
1810 4-amidinophenylmethyl                                                
                 p-toluylsulfonyl                                         
                                OH                                        
1811 3-amidinophenylmethyl                                                
                 n-butyloxycarbonyl                                       
                                OH                                        
1812 3-amidinophenylmethyl                                                
                 n-butyloxycarbonyl                                       
                                OMe                                       
1813 3-amidinophenylmethyl                                                
                 phenylsulfonyl OH                                        
1814 3-amidinophenylmethyl                                                
                 phenylsulfonyl OMe                                       
1815 3-amidinophenylmethyl                                                
                 2-bromophenylsulfonyl                                    
                                OH                                        
1816 3-amidinophenylmethyl                                                
                 2-bromophenylsulfonyl                                    
                                OMe                                       
1817 3-amidinophenylmethyl                                                
                 2-methylphenyl-                                          
                                OH                                        
                 sulfonyl                                                 
1818 3-amidinophenylmethyl                                                
                 2-methylphenyl-                                          
                                OMe                                       
                 sulfonyl                                                 
1819 3-amidinophenylmethyl                                                
                 4-methylphenyl-                                          
                                OH                                        
                 sulfonyl                                                 
1820 3-amidinophenylmethyl                                                
                 4-methylphenyl-                                          
                                OMe                                       
                 sulfonyl                                                 
1821 3-amidinophenylmethyl                                                
                 styrylsulfonyl OH                                        
1822 3-amidinophenylmethyl                                                
                 styrylsulfonyl OMe                                       
1823 3-amidinophenylmethyl                                                
                 benzyloxycarbonyl                                        
                                OH                                        
1824 3-amidinophenylmethyl                                                
                 benzyloxycarbonyl                                        
                                OMe                                       
1825 3-amidinophenylmethyl                                                
                 3,5-dimethyl-  OH                                        
                 isoxazolylsulfonyl                                       
1826 3-amidinophenylmethyl                                                
                 3,5-dimethyl-  OMe                                       
                 isoxazolylsulfonyl                                       
1827 3-amidinophenylmethyl                                                
                 2,4-dimethyl-  OH                                        
                 thiazolylsulfonyl                                        
1828 3-amidinophenylmethyl                                                
                 benzylsulfonyl OH                                        
1829 4-pyridylethyl                                                       
                 n-benzyloxycarbonyl                                      
                                OMe                                       
1830 4-pyridylethyl                                                       
                 n-benzyloxycarbonyl                                      
                                OH                                        
1831 4-pyridylethyl                                                       
                 n-butyloxyoxycarbonyl                                    
                                OMe                                       
1832 4-pyridylethyl                                                       
                 n-butyloxyoxycarbonyl                                    
                                OH                                        
1833 4-pyridylethyl                                                       
                 2-methylphenylsulfonyl                                   
                                OH                                        
1834 4-pyridylethyl                                                       
                 2-methylphenyl-                                          
                                OMe                                       
                 sulfonyl                                                 
1835 4-pyridylethyl                                                       
                 2-bromophenylsulfonyl                                    
                                OH                                        
1836 4-pyridylethyl                                                       
                 2-bromophenylsulfonyl                                    
                                OMe                                       
1837 4-pyridylethyl                                                       
                 3-methylphenyl-                                          
                                OH                                        
                 sulfonyl                                                 
1838 4-pyridylethyl                                                       
                 3,5-dimethyl-  OH                                        
                 isoxazolylsulfonyl                                       
1839 4-pyridylethyl                                                       
                 3,5-dimethyl-  OMe                                       
                 isoxazolylsulfonyl                                       
1840 4-pyridylethyl                                                       
                 2,4-dimethyl-  OH                                        
                 thiazolylsulfonyl                                        
1841 4-pyridylethyl                                                       
                 2,4-dimethyl-  OMe                                       
                 thiazolylsulfonyl                                        
1842 4-pyridylethyl                                                       
                 benzylsulfonyl OH                                        
1843 4-pyridylethyl                                                       
                 styrylsulfonyl OH                                        
1844 4-pyridylethyl                                                       
                 styrylsulfonyl OMe                                       
1845 4-pyridylethyl                                                       
                 2-benzothiophene-                                        
                                OH                                        
                 sulfonyl                                                 
1846 3-pyridylethyl                                                       
                 n-benzyloxycarbonyl                                      
                                OMe                                       
1847 3-pyridylethyl                                                       
                 n-benzyloxycarbonyl                                      
                                OH                                        
1848 3-pyridylethyl                                                       
                 n-butyloxyoxycarbonyl                                    
                                OMe                                       
1849 3-pyridylethyl                                                       
                 n-butyloxyoxycarbonyl                                    
                                OH                                        
1850 3-pyridylethyl                                                       
                 2-methylphenyl-                                          
                                OH                                        
                 sulfonyl                                                 
1851 3-pyridylethyl                                                       
                 2-methylphenyl-                                          
                                OMe                                       
                 sulfonyl                                                 
1852 3-pyridylethyl                                                       
                 2-bromophenylsulfonyl                                    
                                OH                                        
1853 3-pyridylethyl                                                       
                 2-bromophenylsulfonyl                                    
                                OMe                                       
1854 3-pyridylethyl                                                       
                 3-methylphenyl-                                          
                                OH                                        
                 sulfonyl                                                 
1855 3-pyridylethyl                                                       
                 3,5-dimethyl-  OH                                        
1856 3-pyridylethyl                                                       
                 isoxazolylsulfonyl                                       
                                OMe                                       
                 3,5-dimethyl-                                            
                 isoxazolylsulfonyl                                       
1857 3-pyridylethyl                                                       
                 2,4-dimethyl-  OH                                        
                 thiazolylsulfonyl                                        
1858 3-pyridylethyl                                                       
                 2,4-dimethyl-  OMe                                       
                 thiazolylsulfonyl                                        
1859 3-pyridylethyl                                                       
                 benzylsulfonyl OH                                        
1860 3-pyridylethyl                                                       
                 styrylsulfonyl OH                                        
1861 3-pyridylethyl                                                       
                 styrylsulfonyl OMe                                       
1862 3-pyridylethyl                                                       
                 2-benzothiophene-                                        
                                OH                                        
                 sulfonyl                                                 
1863 2-amino-4-pyridylethyl                                               
                 n-benzyloxycarbonyl                                      
                                OMe                                       
1864 2-amino-4-pyridylethyl                                               
                 n-benzyloxycarbonyl                                      
                                OH                                        
1865 2-amino-4-pyridylethyl                                               
                 n-butyloxyoxycarbonyl                                    
                                OMe                                       
1866 2-amino-4-pyridylethyl                                               
                 n-butyloxyoxycarbonyl                                    
                                OH                                        
1867 2-amino-4-pyridylethyl                                               
                 2-methylphenyl-                                          
                                OH                                        
                 sulfonyl                                                 
1868 2-amino-4-pyridylethyl                                               
                 2-methylphenyl OMe                                       
                 sulfonyl                                                 
1869 2-amino-4-pyridylethyl                                               
                 2-bromophenylsulfonyl                                    
                                OH                                        
1870 2-amino-4-pyridylethyl                                               
                 2-bromophenylsulfonyl                                    
                                OMe                                       
1871 2-amino-4-pyridylethyl                                               
                 3-methylphenyl-                                          
                                OH                                        
                 sulfonyl                                                 
1872 2-amino-4-pyridylethyl                                               
                 3,5-dimethyl-  OH                                        
                 isoxazolylsulfonyl                                       
1873 2-amino-4-Pyridylethyl                                               
                 3,5-dimethyl-  OMe                                       
                 isoxazolylsulfonyl                                       
1874 2-amino-4-pyridylethyl                                               
                 2,4-dimethyl-  OH                                        
                 thiazolylsulfonyl                                        
1875 2-amino-4-pyridylethyl                                               
                 2,4-dimethyl-  OMe                                       
                 thiazolylsulfonyl                                        
1876 2-amino-4-pyridylethyl                                               
                 benzylsulfonyl OH                                        
1877 2-amino-4-pyridylethyl                                               
                 benzylsulfonyl OMe                                       
1878 2-amino-4-pyridylethyl                                               
                 styrylsulfonyl OH                                        
1879 2-amino-4-pyridylethyl                                               
                 styrylsulfonyl OMe                                       
1880 2-amino-4-pyridylethyl                                               
                 2-benzothiophene-                                        
                                OH                                        
                 sulfonyl                                                 
1881 6-amino-3-pyridylethyl                                               
                 n-benzyloxycarbonyl                                      
                                OMe                                       
1882 6-amino-3-pyridylethyl                                               
                 n-benzyloxycarbonyl                                      
                                OH                                        
1883 6-amino-3-pyridylethyl                                               
                 n-butyloxyoxycarbonyl                                    
                                OMe                                       
1884 6-amino-3-pyridylethyl                                               
                 n-butyloxyoxycarbonyl                                    
                                OH                                        
1885 6-amino-3-pyridylethyl                                               
                 2-methylphenyl-                                          
                                OH                                        
                 sulfonyl                                                 
1886 6-amino-3-pyridylethyl                                               
                 2-methylphenyl-                                          
                                OMe                                       
                 sulfonyl                                                 
1887 6-amino-3-pyridylethyl                                               
                 2-bromophenylsulfonyl                                    
                                OH                                        
1888 6-amino-3-pyridylethyl                                               
                 2-bromophenylsulfonyl                                    
                                OMe                                       
1889 6-amino-3-pyridylethyl                                               
                 3-methylphenyl-                                          
                                OH                                        
                 sulfonyl                                                 
1890 6-amino-3-pyridylethyl                                               
                 3,5-dimethyl-  OH                                        
                 isoxazolylsulfonyl                                       
1891 6-amino-3-pyridylethyl                                               
                 3,5-dimethyl-  OMe                                       
                 isoxazolylsulfonyl                                       
1892 6-amino-3-pyridylethyl                                               
                 2,4-dimethyl-  OH                                        
                 thiazolylsulfonyl                                        
1893 6-amino-3-pyridylethyl                                               
                 2,4-dimethyl-  OMe                                       
                 thiazolylsulfonyl                                        
1894 6-amino-3-pyridylethyl                                               
                 benzylsulfonyl OH                                        
1895 6-amino-3-pyridylethyl                                               
                 benzylsulfonyl OMe                                       
1896 6-amino-3-pyridylethyl                                               
                 styrylsulfonyl OH                                        
1897 6-amino-3-pyridylethyl                                               
                 styrylsulfonyl OMe                                       
1898 6-amino-4-pyridylethyl                                               
                 2-benzothiophene-                                        
                                OH                                        
                 sulfonyl                                                 
1899 2-amidino-4-pyridylethyl                                             
                 n-benzyloxycarbonyl                                      
                                OMe                                       
1900 2-amidino-4-pyridylethyl                                             
                 n-benzyloxycarbonyl                                      
                                OH                                        
1901 2-amidino-4-pyridylethyl                                             
                 n-butyloxyoxycarbonyl                                    
                                OMe                                       
1902 2-amidino-4-pyridylethyl                                             
                 n-butyloxyoxycarbonyl                                    
                                OH                                        
1903 2-amidino-4-pyridylethyl                                             
                 2-methylphenyl-                                          
                                OH                                        
                 sulfonyl                                                 
1904 2-amidino-4-pyridylethyl                                             
                 2-methylphenyl-                                          
                                OMe                                       
                 sulfonyl                                                 
1905 2-amidino-4-pyridylethyl                                             
                 2-bromophenylsulfonyl                                    
                                OH                                        
1906 2-amidino-4-pyridylethyl                                             
                 2-bromophenylsulfonyl                                    
                                OMe                                       
1907 2-amidino-4-pyridylethyl                                             
                 3-methylphenyl-                                          
                                OH                                        
                 sulfonyl                                                 
1908 2-amidino-4-pyridylethyl                                             
                 3,5-dimethyl-  OH                                        
                 isoxazolylsulfonyl                                       
1909 2-amidino-4-pyridylethyl                                             
                 3,5-dimethyl-  OMe                                       
                 isoxazolylsulfonyl                                       
1910 2-amidino-4-pyridylethyl                                             
                 2,4-dimethyl-  OH                                        
                 thiazolylsulfonyl                                        
1911 2-amidino-4-pyridylethyl                                             
                 2,4-dimethyl-  OMe                                       
                 thiazolylsulfonyl                                        
1912 2-amidino-4-pyridylethyl                                             
                 benzylsulfonyl OH                                        
1913 2-amidino-4-pyridylethyl                                             
                 benzylsulfonyl OMe                                       
1914 2-amidino-4-pyridylethyl                                             
                 styrylsulfonyl OH                                        
1915 2-amidino-4-pyridylethyl                                             
                 styrylsulfonyl OMe                                       
1916 2-amidino-4-pyridylethyl                                             
                 2-benzothiophene-                                        
                                OH                                        
                 sulfonyl                                                 
1917 6-amidino-3-pyridylethyl                                             
                 n-benzyloxycarbonyl                                      
                                OMe                                       
1918 6-amidino-3-pyridylethyl                                             
                 n-benzyloxycarbonyl                                      
                                OH                                        
1919 6-amidino-3-pyridylethyl                                             
                 n-butyloxyoxycarbonyl                                    
                                OMe                                       
1920 6-amidino-3-pyridylethyl                                             
                 n-butyloxyoxycarbonyl                                    
                                OH                                        
1921 6-amidino-3-pyridylethyl                                             
                 2-methylphenyl-                                          
                                OH                                        
                 sulfonyl                                                 
1922 6-amidino-3-pyridylethyl                                             
                 2-methylphenyl-                                          
                                OMe                                       
1923 6-amidino-3-pyridylethyl                                             
                 2-bromophenylsulfonyl                                    
                                OH                                        
1924 6-amidino-3-pyridylethyl                                             
                 2-bromophenylsulfonyl                                    
                                OMe                                       
1925 6-amidino-3-pyridylethyl                                             
                 3-methylphenyl-                                          
                                OH                                        
                 sulfonyl                                                 
1926 6-amidino-3-pyridylethyl                                             
                 3,5-dimethyl-  OH                                        
                 isoxazolylsulfonyl                                       
1927 6-amidino-3-pyridylethyl                                             
                 3,5-dimethyl-  OMe                                       
                 isoxazolylsulfonyl                                       
1928 6-amidino-3-pyridylethyl                                             
                 2,4-dimethyl-  OH                                        
                 thiazolylsulfonyl                                        
1929 6-amidino-3-pyridylethyl                                             
                 2,4-dimethyl-  OMe                                       
                 thiazolylsulfonyl                                        
1930 6-amidino-3-pyridylethyl                                             
                 benzylsulfonyl OH                                        
1931 6-amidino-3-pyridylethyl                                             
                 benzylsulfonyl Me                                        
1932 6-amidino-3-pyridylethyl                                             
                 styrylsulfonyl OH                                        
1933 6-amidino-3-pyridylethyl                                             
                 styrylsulfonyl OMe                                       
1934 6-amidino-3-pyridylethyl                                             
                 2-benzothiophene-                                        
                                OH                                        
                 sulfonyl                                                 
1935 4-amidino-2-fluoro-                                                  
                 2-methylphenylsulfonyl                                   
                                OH                                        
     phenyl                                                               
1936 4-amidino-2-fluoro-                                                  
                 3,5-dimethylisoxazolyl-                                  
                                OH                                        
     phenyl      sulfonyl                                                 
1937 2-amidino-5-pyridyl                                                  
                 2-methylphenylsulfonyl                                   
                                OH                                        
1938 2-amidino-5-pyridyl                                                  
                 2-bromophenylsulfonyl                                    
                                OH                                        
1939 2-amidino-5-pyridyl                                                  
                 i-butyloxycarbonyl                                       
                                OMe                                       
1940 2-amidino-5-pyridyl                                                  
                 3,5-dimethylisoxazolyl-                                  
                                OH                                        
                 sulfonyl                                                 
1941 3-amidino-6-pyridyl                                                  
                 2-methylphenylsulfonyl                                   
                                OH                                        
1942 3-amidino-6-pyridyl                                                  
                 2-bromophenylsulfonyl                                    
                                OMe                                       
1943 3-amidino-6-pyridyl                                                  
                 2,5-dimethylthiazolyl-                                   
                                OH                                        
                 sulfonyl                                                 
1944 3-amidino-6-pyridyl                                                  
                 3,5-dimethylisoxazolyl-                                  
                                OH                                        
                 sulfonyl                                                 
1945 4-piperidinylethyl                                                   
                 3-methylphenylsulfonyl                                   
                                OH  481                                   
1946 4-(N-2-methoxybenzyl)-                                               
                 2-methylphenylsulfonyl                                   
                                OMe 622.3                                 
     amidinophenyl HCl                                                    
1947 4-(N-2-methoxybenzyl)-                                               
                 2-methylphenylsulfonyl                                   
                                OH  608.3                                 
     amidinophenyl TFA                                                    
1948 4-(N-n-butyl)-                                                       
                 2-methylphenylsulfonyl                                   
                                OMe 558.4                                 
     amidinophenyl                                                        
1949 4-(N-n-butyl)-                                                       
                 2-methylphenylsulfonyl                                   
                                OH  544.4                                 
     amidinophenyl                                                        
1950 4-(N-ethyl)-                                                         
                 2-methylphenylsulfonyl                                   
                                OMe 530.3                                 
     amidinophenyl                                                        
1951 4-(N-ethyl)-                                                         
     amidinophenyl                                                        
                 2-methylphenylsulfonyl                                   
                                OH  516.3                                 
1952 4-amidinophenoxymethyl                                               
                 benzyloxycarbonyl                                        
                                OMe                                       
1953 4-amidinophenoxymethyl                                               
                 benzyloxycarbonyl                                        
                                OH                                        
1954 4-amidinophenoxymethyl                                               
                 n-butyloxycarbonyl                                       
                                OMe                                       
1955 4-amidinophenoxymethyl                                               
                 n-butyloxycarbonyl                                       
                                OH                                        
1956 4-amidinophenoxymethyl                                               
                 cyclopropylethoxy                                        
                                OMe                                       
                 carbonyl                                                 
1957 4-amidinophenoxymethyl                                               
                 cyclopropylethoxy                                        
                                OH                                        
                 carbonyl                                                 
1958 4-amidinophenoxymethyl                                               
                 4-methylphenylsulfonyl                                   
                                OMe                                       
1959 4-amidinophenoxymethyl                                               
                 4-methylphenylsulfonyl                                   
                                OH                                        
1960 4-amidinophenoxymethyl                                               
                 3-methylphenylsulfonyl                                   
                                OMe                                       
1961 4-amidinophenoxymethyl                                               
                 3-methylphenylsulfonyl                                   
                                OH                                        
1962 4-amidinophenoxymethyl                                               
                 n-butylsulfonyl                                          
                                OMe                                       
1963 4-amidinophenoxymethyl                                               
                 n-butylsulfonyl                                          
                                OH                                        
1964 4-amidinophenoxy                                                     
                 benzyloxycarbonyl                                        
                                OMe                                       
1965 4-amidinophenoxy                                                     
                 benzyloxycarbonyl                                        
                                OH                                        
1967 4-amidinophenoxy                                                     
                 n-butyloxycarbonyl                                       
                                OMe                                       
1968                                                                      
1969 4-amidinophenoxy                                                     
                 n-butyloxycarbonyl                                       
                                OH                                        
1970 4-amidinophenoxy                                                     
                 cyclopropylethyoxy                                       
                                OHe                                       
                 carbonyl                                                 
1971 4-amidinophenoxy                                                     
                 cyclopropylethoxy                                        
                                OH                                        
1972 4-amidinophenoxy                                                     
                 carbonyl                                                 
                 4-methylphenylsulfonyl                                   
                                OMe                                       
1973 4-amidinophenoxy                                                     
                 4-methylphenylsulfonyl                                   
                                OH                                        
1974 4-amidinophenoxy                                                     
                 3-methylphenylsulfonyl                                   
                                OMe                                       
1975 4-amidinophenoxy                                                     
                 3-methylphenylsulfonyl                                   
                                OH                                        
1976 4-amidinophenoxy                                                     
                 n-butylsulfonyl                                          
                                OMe                                       
1977 4-amidinophenoxy                                                     
                 n-butylsulfonyl                                          
                                OH                                        
1978 4-amidinophenethyl                                                   
                 benzyloxycarbonyl                                        
                                OMe                                       
1979 4-amidinophenethyl                                                   
                 benzyloxycarbonyl                                        
                                OH                                        
1980 4-amidinophenethyl                                                   
                 n-butyloxycarbonyl                                       
                                OMe                                       
1981 4-amidinophenethyl                                                   
                 n-butyloxycarbonyl                                       
                                OH                                        
1982 4-amidinophenethyl                                                   
                 cyclopropylethoxy                                        
                                OMe                                       
                 carbonyl                                                 
1983 4-amidinophenethyl                                                   
                 cyclopropylethoxy                                        
                                OH                                        
                 carbonyl                                                 
1984 4-amidinophenethyl                                                   
                 4-methylphenylsulfonyl                                   
                                OMe                                       
1985 4-amidinophenethyl                                                   
                 4-methylphenylsulfonyl                                   
                                OH                                        
1986 4-amidinophenethyl                                                   
                 3-methylphenylsulfonyl                                   
                                OMe                                       
1987 4-amidinophenethyl                                                   
                 3-methylphenylsulfonyl                                   
                                OH                                        
1988 4-amidinophenethyl                                                   
                 n-butylsulfonyl                                          
                                OMe                                       
1989 4-amidinophenethyl                                                   
                 n-butylsulfonyl                                          
                                OH                                        
1990 N-(4-amidinophenyl)                                                  
                 benzyloxycarbonyl                                        
                                OMe                                       
     aminomethyl                                                          
1991 N-(4-amidinophenyl)                                                  
                 benzyloxycarbonyl                                        
                                OH                                        
     aminomethyl                                                          
1993 N-(4-amidinophenyl)                                                  
                 n-butyloxycarbonyl                                       
                                OMe                                       
     aminomethyl                                                          
1994 N-(4-amidinophenyl)                                                  
                 n-butyloxycarbonyl                                       
                                OH                                        
     aminomethyl                                                          
1995 N-(4-amidinophenyl)                                                  
                 cyclopropylethoxy                                        
                                OH                                        
     aminomethyl carbonyl                                                 
1996 N-(4-amidinophenyl)                                                  
                 4-methylphenylsulfonyl                                   
                                OMe                                       
     aminomethyl                                                          
1997 N-(4-amidinophenyl)                                                  
                 4-methylphenylsulfonyl                                   
                                OH                                        
     aminomethyl                                                          
1998 N-(4-amidinophenyl)                                                  
                 3-methylphenylsulfonyl                                   
                                OMe                                       
     aminomethyl                                                          
1999 N-(4-amidinophenyl)                                                  
                 3-methylphenylsulfonyl                                   
                                OH                                        
     aminomethyl                                                          
2000 N-(4-amidinophenyl)                                                  
                 n-butylsulfonyl                                          
                                OMe                                       
     aminomethyl                                                          
2001 N-(4-amidinophenyl)                                                  
                 n-butylsulfonyl                                          
                                OH                                        
     aminomethyl                                                          
2002 4-amidinophenyl                                                      
                 benzyloxycarbonyl                                        
                                OMe                                       
     methylamino                                                          
2003 4-amidinophenyl                                                      
                 benzyloxycarbonyl                                        
                                OH                                        
     methylamino                                                          
2004 4-amidinophenyl                                                      
                 n-butyloxycarbonyl                                       
                                OMe                                       
     methylamino                                                          
2005 4-amidinophenyl                                                      
                 n-butyloxycarbonyl                                       
                                OH                                        
     methylamino                                                          
2006 4-amidinophenyl                                                      
                 cyclopropylethoxy                                        
                                OMe                                       
     methylamino carbonyl                                                 
2007 4-amidinophenyl                                                      
                 cyclopropylethoxy                                        
                                OH                                        
     methylamino carbonyl                                                 
2008 4-amidinophenyl                                                      
                 4-methylphenylsulfonyl                                   
                                OMe                                       
     methylamino                                                          
2010 4-amidinophenyl                                                      
                 4-methylphenylsulfonyl                                   
                                OH                                        
     methylamino                                                          
2011 4-amidinophenyl                                                      
                 3-methylphenylsulfonyl                                   
                                OMe                                       
     methylamino                                                          
2012 4-amidinophenyl                                                      
                 n-butylsulfonyl                                          
                                OMe                                       
     methylamino                                                          
2013 4-amidinophenyl                                                      
                 n-butylsulfonyl                                          
                                OH                                        
     methylamino                                                          
2014 N-(4-amidinophenyl)                                                  
                 benzyloxycarbonyl                                        
                                OMe                                       
     aminocarbonyl                                                        
2015 N-(4-amidinophenyl)                                                  
                 benzyloxycarbonyl                                        
                                OH                                        
     aminocarbonyl                                                        
2016 N-(4-amidinophenyl)                                                  
                 n-butyloxycarbonyl                                       
                                OMe                                       
     aminocarbonyl                                                        
2017 N-(4-amidinophenyl)                                                  
                 n-butyloxycarbonyl                                       
                                OH                                        
     aminocarbonyl                                                        
2018 N-(4-amidinophenyl)                                                  
                 cyclopropylethoxy                                        
                                OMe                                       
     aminocarbonyl                                                        
                 carbonyl                                                 
2019 N-(4-amidinophenyl)                                                  
                 cyclopropylethoxy                                        
                                OH                                        
     aminocarbonyl                                                        
                 carbonyl                                                 
2020 N-(4-amidinophenyl)                                                  
                 4-methylphenylsulfonyl                                   
                                OMe                                       
     aminocarbonyl                                                        
2021 N-(4-amidinophenyl)                                                  
                 4-methylphenylsulfonyl                                   
                                OH                                        
     aminocarbonyl                                                        
2022 N-(4-amidinophenyl)                                                  
                 3-methylphenylsulfonyl                                   
                                OMe                                       
     aminocarbonyl                                                        
2023 N-(4-amidinophenyl)                                                  
                 3-methylphenylsulfonyl                                   
                                OH                                        
     aminocarbonyl                                                        
2024 N-(4-amidinophenyl)                                                  
                 n-butylsulfonyl                                          
                                OMe                                       
     aminocarbonyl                                                        
2025 N-(4-amidinophenyl)                                                  
                 n-butylsulfonyl                                          
                                OH                                        
     aminocarbonyl                                                        
2027 4-amidinophenyl                                                      
                 benzyloxycarbonyl                                        
                                OMe                                       
     carbonylamino                                                        
2028 4-amidinophenyl                                                      
                 benzyloxycarbonyl                                        
                                OH                                        
     carbonylamino                                                        
2029 4-amidinophenyl                                                      
                 n-butyloxycarbonyl                                       
                                OMe                                       
     carbonylamino                                                        
2030 4-amidinophenyl                                                      
                 n-butyloxycarbonyl                                       
                                OH                                        
     carbonylamino                                                        
2031 4-amidinophenyl                                                      
                 cyclopropylethoxy                                        
                                OMe                                       
     carbonylamino                                                        
                 carbonyl                                                 
2032 4-amidinophenyl                                                      
                 cyclopropylethoxy                                        
                                OH                                        
     carbonylamino                                                        
                 carbonyl                                                 
2033 4-amidinophenyl                                                      
                 4-methylphenylsulfonyl                                   
                                OMe                                       
     carbonylamino                                                        
2034 4-amidinophenyl                                                      
                 4-methylphenylsulfonyl                                   
                                OH                                        
     carbonylamino                                                        
2035 4-amidinophenyl                                                      
                 3-methylphenylsulfonyl                                   
                                OMe                                       
     carbonylamino                                                        
2036 4-amidinophenyl                                                      
                 3-methylphenylsulfonyl                                   
                                OH                                        
     carbonylamino                                                        
2037 4-amidinophenyl                                                      
                 n-butylsulfonyl                                          
                                OMe                                       
     carbonylamino                                                        
2038 4-amidinophenyl                                                      
                 n-butylsulfonyl                                          
                                OH                                        
     carbonylamino                                                        
2039 N-(4-amidinophenyl)                                                  
                 benzyloxycarbonyl                                        
                                OMe                                       
     amino                                                                
2040 N-(4-amidinophenyl)                                                  
                 benzyloxycarbonyl                                        
                                OH                                        
     amino                                                                
2041 N-(4-amidinophenyl)                                                  
                 n-butyloxycarbonyl                                       
                                OMe                                       
     amino                                                                
2042 N-(4-amidinophenyl)                                                  
                 n-butyloxycarbonyl                                       
                                OH                                        
     amino                                                                
2044 N-(4-amidinophenyl)                                                  
                 cyclopropylethoxy                                        
                                OMe                                       
     amino       carbonyl                                                 
2045 N-(4-amidinophenyl)                                                  
                 cyclopropylethoxy                                        
                                OH                                        
     amino       carbonyl                                                 
2046 N-(4-amidinophenyl)                                                  
                 4-methylphenylsulfonyl                                   
                                OMe                                       
     amino                                                                
2047 N-(4-amidinophenyl)                                                  
                 4-methylphenylsulfonyl                                   
                                OH                                        
     amino                                                                
2048 N-(4-amidinophenyl)                                                  
                 3-methylphenylsulfonyl                                   
                                OMe                                       
     amino                                                                
2049 N-(4-amidinophenyl)                                                  
                 3-methylphenylsulfonyl                                   
                                OH                                        
     amino                                                                
2050 N-(4-amidinophenyl)                                                  
                 n-butylsulfonyl                                          
                                OMe                                       
     amino                                                                
2051 N-(4-amidinophenyl)                                                  
                 n-butylsulfonyl                                          
                                OH                                        
     amino                                                                
2052 N-(4-amidinophenyl)-N-                                               
                 benzyloxycarbonyl                                        
                                OMe                                       
     methylamino                                                          
2053 N-(4-amidinophenyl)-N-                                               
                 benzyloxycarbonyl                                        
                                OH                                        
     methylamino                                                          
2054 N-(4-amidinophenyl)-N-                                               
                 n-butyloxycarbonyl                                       
                                OMe                                       
     methylamino                                                          
2055 N-(4-amidinophenyl)-N-                                               
                 n-butyloxycarbonyl                                       
                                OH                                        
     methylamino                                                          
2056 N-(4-amidinophenyl)-N-                                               
                 cyclopropylethoxy                                        
                                OMe                                       
     methylamino carbonyl                                                 
2057 N-(4-amidinophenyl)-N-                                               
                 cyclopropylethoxy                                        
                                OH                                        
     methylamino carbonyl                                                 
2058 N-(4-amidinophenyl)-N-                                               
                 4-methylphenylsulfonyl                                   
                                OMe                                       
     methylamino                                                          
2059 N-(4-amidinophenyl)-N-                                               
                 4-methylphenylsulfonyl                                   
                                OH                                        
     methylamino                                                          
2061 N-(4-amidinophenyl)-N-                                               
                 3-methylphenylsulfonyl                                   
                                OMe                                       
     methylamino                                                          
2062 N-(4-amidinophenyl)-N-                                               
                 3-methylphenylsulfonyl                                   
                                OH                                        
     methylamino                                                          
2063 N-(4-amidinophenyl)-N-                                               
                 n-butylsulfonyl                                          
                                OMe                                       
     methylamino                                                          
2064 N-(4-amidinophenyl)-N-                                               
                 n-butylsulfonyl                                          
                                OH                                        
     methylamino                                                          
2065 4-amidinobenzoyl                                                     
                 benzyloxycarbonyl                                        
                                OMe                                       
2066 4-amidinobenzoyl                                                     
                 benzyloxycarbonyl                                        
                                OH                                        
2067 4-amidinobenzoyl                                                     
                 n-butyloxycarbonyl                                       
                                OMe                                       
2068 4-amidinobenzoyl                                                     
                 n-butyloxycarbonyl                                       
                                OH                                        
2069 4-amidinobenzoyl                                                     
                 cyclopropylethoxy                                        
                                OMe                                       
                 carbonyl                                                 
2070 4-amidinobenzoyl                                                     
                 cyclopropylethoxy                                        
                                OH                                        
                 carbonyl                                                 
2071 4-amidinobenzoyl                                                     
                 4-methylphenylsulfonyl                                   
                                OMe                                       
2072 4-amidinobenzoyl                                                     
                 4-methylphenylsulfonyl                                   
                                OH                                        
2073 4-amidinobenzoyl                                                     
                 3-methylphenylsulfonyl                                   
                                OMe                                       
2074 4-amidinobenzoyl                                                     
                 3-methylphenylsulfonyl                                   
                                OH                                        
2075 4-amidinobenzoyl                                                     
                 n-butylsulfonyl                                          
                                OMe                                       
2076 4-amidinobenzoyl                                                     
                 n-butylsulfonyl                                          
                                OH                                        
2077 4-amidinophenyl                                                      
                 benzyloxycarbonyl                                        
                                OMe                                       
     methylcarbonyl                                                       
2078 4-amidinophenyl                                                      
                 benzyloxycarbonyl                                        
                                OH                                        
     methylcarbonyl                                                       
2079 4-amidinophenyl                                                      
                 n-butyloxycarbonyl                                       
                                OMe                                       
     methylcarbonyl                                                       
2080 4-amidinophenyl                                                      
                 n-butyloxycarbonyl                                       
                                OH                                        
     methylcarbonyl                                                       
2081 4-amidinophenyl                                                      
                 cyclopropylethoxy                                        
                                OMe                                       
     methylcarbonyl                                                       
                 carbonyl                                                 
2083 4-amidinophenyl                                                      
                 cyclopropylethoxy                                        
                                OH                                        
     methylcarbonyl                                                       
                 carbonyl                                                 
2084 4-amidinophenyl                                                      
                 4-methylphenylsulfonyl                                   
                                OMe                                       
     methylcarbonyl                                                       
2085 4-amidinophenyl                                                      
                 4-methylphenylsulfonyl                                   
                                OH                                        
     methylcarbonyl                                                       
2086 4-amidinophenyl                                                      
                 3-methylphenylsulfonyl                                   
                                OMe                                       
     methylcarbonyl                                                       
2087 4-amidinophenyl                                                      
                 3-methylphenylsulfonyl                                   
                                OH                                        
     methylcarbonyl                                                       
2088 4-amidinophenyl                                                      
                 n-butylsulfonyl                                          
                                OMe                                       
     methylcarbonyl                                                       
2089 4-amidinophenyl                                                      
                 n-butylsulfonyl                                          
                                OH                                        
     methylcarbonyl                                                       
2090 4-amidinophenyl-                                                     
                 benzyloxycarbonyl                                        
                                OMe                                       
     carbonylmethyl                                                       
2091 4-amidinophenyl-                                                     
                 benzyloxycarbonyl                                        
                                OH                                        
     carbonylmethyl                                                       
2092 4-amidinophenyl-                                                     
                 n-butyloxycarbonyl                                       
                                OMe                                       
     carbonylmethyl                                                       
2093 4-amidinophenyl-                                                     
                 n-butyloxycarbonyl                                       
                                OH                                        
     carbonylmethyl                                                       
2094 4-amidinophenyl                                                      
                 cyclopropylethoxy                                        
                                OMe                                       
     carbonylmethyl                                                       
                 carbonyl                                                 
2095 4-amidinophenyl                                                      
                 cyclopropylethoxy                                        
                                OH                                        
     carbonylmethyl                                                       
                 carbonyl                                                 
2096 4-amidinophenyl                                                      
                 4-methylphenylsulfonyl                                   
                                OMe                                       
     carbonylmethyl                                                       
2097 4-amidinophenyl-                                                     
                 4-methylphenylsulfonyl                                   
                                OH                                        
     carbonylmethyl                                                       
2098 4-amidinophenyl-                                                     
                 3-methylphenylsulfonyl                                   
                                OMe                                       
     carbonylmethyl                                                       
2100 4-amidinophenyl-                                                     
                 3-methylphenylsulfonyl                                   
                                OH                                        
     carbonylmethyl                                                       
2101 4-amidinophenyl-                                                     
                 n-butylsulfonyl                                          
                                OMe                                       
     carbonylmethyl                                                       
2102 4-amidinophenyl-                                                     
                 n-butylsulfonyl                                          
                                OH                                        
     carbonylmethyl                                                       
2103 4-amidinophenyl                                                      
                 3,5-dimethylisoxazol-                                    
                                OMe HNMR                                  
     HOAc salt, 5(R),N.sup.2 (S)                                          
                 4-ylsulfonyl                                             
     isomer                                                               
2104 4-amidinophenyl                                                      
                 3,5-dimethylisoxazol-                                    
                                OH  493                                   
     TFA salt, 5(R),N.sup.2 (S)                                           
                 4-ylsulfonyl                                             
     isomer                                                               
2105 4-amidinophenyl                                                      
                 3,5-dimethylisoxazol                                     
                                OMe HNMR                                  
     HOAc salt, 5(S),N.sup.2 (S)                                          
                 4-ylsulfonyl                                             
     isomer                                                               
2106 4-amidinophenyl                                                      
                 3,5-dimethylisoxazol-                                    
                                OH                                        
     TFA salt, 5(S),N.sup.2 (S)                                           
                 4-ylsulfonyl                                             
     isomer                                                               
2107 4-amidinophenyl                                                      
                 3,5-dimethylisoxazol-                                    
                                OMe                                       
     HOAc salt, 5(R),N.sup.2 (R)                                          
                 4-ylsulfonyl                                             
     isomer                                                               
2108 4-amidinophenyl                                                      
                 3,5-dimethylisoxazol                                     
                                OMe                                       
     HOAc salt, 5(S),N.sup.2 (R)                                          
                 4-ylsulfonyl                                             
     isomer                                                               
2109 2-guanidinoethyl                                                     
                 carbobenzyloxy OH  435                                   
2110 5-guanidinovaleryl                                                   
                 carbobenzyloxy OH  477                                   
2111 4-(N-2-     2-methylphenylsulfonyl                                   
                                OMe 622                                   
     methoxybenyzyl)-                                                     
     amidinophenyl ·HCl                                          
2112 4-(N-2-                                                              
     methoxybenyzyl)-                                                     
                 2-methylphenylsulfonyl                                   
                                OH  608                                   
     amidinophenyl ·HCl                                          
2113 4-(N-n-butyl)-                                                       
                 2-methylphenylsulfonyl                                   
                                OMe 558                                   
     amidinophenyl ·TFA                                          
2114 4-(N-n-butyl)-                                                       
                 2-methylphenylsulfonyl                                   
                                OH  544                                   
     amidinophenyl ·TFA                                          
2115 4-(N-ethyl)-                                                         
                 2-methylphenylsulfonyl                                   
                                OMe 530                                   
     amidinophenyl ·TFA                                          
2116 4-(N-ethyl)-                                                         
                 2-methylphenylsulfonyl                                   
                                OH  516                                   
     amidinophenyl ·TFA                                          
2117 4-amidinophenyl                                                      
                 4-methyl-2-methylcarbonylamino-                          
                                OH  566                                   
                 5-thiazolylsulfonyl ·TFA                        
2118 4-amidinophenyl                                                      
                 5-phenylsulfonyl-2-                                      
                                OMe 634                                   
                 thienylsulfonyl·TFA                             
2119 4-amidinophenyl                                                      
                 5-phenylsulfonyl-2-                                      
                                OMe 620                                   
                 thienylsulfonyl·TFA                             
2120 N-t-butyloxycarbonyl-4-                                              
                 5-phenylsulfonyl-2-                                      
                                OH  720                                   
     amidinophenyl                                                        
                 thienylsulfonyl·TFA                             
__________________________________________________________________________

                                  TABLE 10                                
__________________________________________________________________________
 ##STR362##                                                               
Ex.                                 MS                                    
No. R.sup.1 --V                                                           
               R.sup.5a                                                   
                    R.sup.16     Y  (M +  H)                              
__________________________________________________________________________
2121                                                                      
    4-piperidinylethyl                                                    
               methyl                                                     
                    benzyloxycarbonyl                                     
                                 OH                                       
2122                                                                      
    4-piperidinylethyl                                                    
               methyl                                                     
                    2-methylphenylsulfonyl                                
                                 OH                                       
2123                                                                      
    4-piperidinylethyl                                                    
               methyl                                                     
                    3,5-dimethylisoxazolyl                                
                                 OH                                       
                    sulfonyl                                              
2124                                                                      
    4-piperidinylethyl                                                    
               methyl                                                     
                    n-butylsulfonyl                                       
                                 OH                                       
2125                                                                      
    4-piperidinylethyl                                                    
               methyl                                                     
                    n-butylsulfonyl                                       
                                 OMe                                      
2126                                                                      
    4-piperidinylmethyl                                                   
               methyl                                                     
                    n-butylsulfonyl                                       
                                 OH                                       
2127                                                                      
    4-piperidinylmethyl                                                   
               methyl                                                     
                    n-butylsulfonyl                                       
                                 OMe                                      
2128                                                                      
    4-piperidinylmethyl                                                   
               methyl                                                     
                    2-methylphenylsulfonyl                                
                                 OH                                       
2129                                                                      
    4-piperidinylmethyl                                                   
               methyl                                                     
                    2-bromophenylsulfonyl                                 
                                 OH                                       
2130                                                                      
    4-piperidinylmethyl                                                   
               methyl                                                     
                    3-methylphenylsulfonyl                                
                                 OH                                       
2131                                                                      
    4-piperidinylmethyl                                                   
               methyl                                                     
                    3-methylphenylsulfonyl                                
                                 OMe                                      
2132                                                                      
    4-piperidinylmethyl                                                   
               methyl                                                     
                    3,5-dimethylisoxazolyl                                
                                 OH                                       
                    sulfonyl                                              
2133                                                                      
    4-piperidinylmethyl                                                   
               methyl                                                     
                    3,5-dimethylisoxazolyl                                
                                 OMe                                      
                    sulfonyl                                              
2134                                                                      
    4-piperidinylmethyl                                                   
               methyl                                                     
                    styrylsulfonyl                                        
                                 OH                                       
2135                                                                      
    4-piperidinylmethyl                                                   
               methyl                                                     
                    benzyloxycarbonyl                                     
                                 OH                                       
2136                                                                      
    4-piperidinylmethyl                                                   
               methyl                                                     
                    benzyloxycarbonyl                                     
                                 OMe                                      
2137                                                                      
    4-piperidinylmethyl                                                   
               methyl                                                     
                    n-butyloxycarbonyl                                    
                                 OH                                       
2138                                                                      
    4-piperidinylmethyl                                                   
               methyl                                                     
                    n-butyloxycarbonyl                                    
                                 OMe                                      
2139                                                                      
    4-piperidinylpropyl                                                   
               methyl                                                     
                    n-butylsulfonyl                                       
                                 OH                                       
2140                                                                      
    4-piperidinylpropyl                                                   
               methyl                                                     
                    n-butylsulfonyl                                       
                                 OMe                                      
2141                                                                      
    4-piperidinylpropyl                                                   
               methyl                                                     
                    2-methylphenylsulfonyl                                
                                 OH                                       
2142                                                                      
    4-piperidinylpropyl                                                   
               methyl                                                     
                    2-bromophenylsulfonyl                                 
                                 OH                                       
2143                                                                      
    4-piperidinylpropyl                                                   
               methyl                                                     
                    3-methylphenylsulfonyl                                
                                 OH                                       
2144                                                                      
    4-piperidinylpropyl                                                   
               methyl                                                     
                    3-methylphenylsulfonyl                                
                                 OMe                                      
2145                                                                      
    4-piperidinylpropyl                                                   
               methyl                                                     
                    3,5-dimethylisoxazolyl                                
                                 OH                                       
                    sulfonyl                                              
2146                                                                      
    4-piperidinylpropyl                                                   
               methyl                                                     
                    3,5-dimethylisoxazolyl                                
                                 OMe                                      
                    sulfonyl                                              
2147                                                                      
    4-piperidinylpropyl                                                   
               methyl                                                     
                    styrylsulfonyl                                        
                                 OH                                       
2148                                                                      
    4-piperidinylpropyl                                                   
               methyl                                                     
                    benzyloxycarbonyl                                     
                                 OH                                       
2149                                                                      
    4-piperidinylpropyl                                                   
               methyl                                                     
                    benzyloxycarbonyl                                     
                                 OMe                                      
2150                                                                      
    4-piperidinylpropyl                                                   
               methyl                                                     
                    n-butyloxycarbonyl                                    
                                 OH                                       
2151                                                                      
    4-piperidinylpropyl                                                   
               methyl                                                     
                    n-butyloxycarbonyl                                    
                                 OMe                                      
2152                                                                      
    4-amidinopiperidinyl                                                  
               methyl                                                     
                    n-butylsulfonyl                                       
                                 OH                                       
2153                                                                      
    4-amidinopiperidinyl                                                  
               methyl                                                     
                    n-butylsulfonyl                                       
                                 OMe                                      
2154                                                                      
    4-amidinopiperidinyl                                                  
               methyl                                                     
                    2-methylphenylsulfonyl                                
                                 OH                                       
2155                                                                      
    4-amidinopiperidinyl                                                  
               methyl                                                     
                    2-bromophenylsulfonyl                                 
                                 OH                                       
2156                                                                      
    4-amidinopiperidinyl                                                  
               methyl                                                     
                    3-methylphenylsulfonyl                                
                                 OH                                       
2157                                                                      
    4-amidinopiperidinyl                                                  
               methyl                                                     
                    3-methylphenylsulfonyl                                
                                 OMe                                      
2158                                                                      
    4-amidinopiperidinyl                                                  
               methyl                                                     
                    3,5-dimethylisoxazolyl                                
                                 OH                                       
                    sulfonyl                                              
2159                                                                      
    4-amidinopiperidinyl                                                  
               methyl                                                     
                    3,5-dimethylisoxazolyl                                
                                 OMe                                      
                    sulfonyl                                              
2160                                                                      
    4-amidinopiperidinyl                                                  
               methyl                                                     
                    styrylsulfonyl                                        
                                 OH                                       
2161                                                                      
    4-amidinopiperidinyl                                                  
               methyl                                                     
                    benzyloxycarbonyl                                     
                                 OH .                                     
2162                                                                      
    4-amidinopiperidinyl                                                  
               methyl                                                     
                    benzyloxycarbonyl                                     
                                 OMe                                      
2163                                                                      
    4-amidinopiperidinyl                                                  
               methyl                                                     
                    n-butyloxycarbonyl                                    
                                 OH                                       
2164                                                                      
    4-amidinopiperidinyl                                                  
               methyl                                                     
                    n-butyloxycarbonyl                                    
                                 OMe                                      
2165                                                                      
    4-amidinopiperidinyl-                                                 
               methyl                                                     
                    n-butylsulfonyl                                       
                                 OH                                       
    methyl                                                                
2166                                                                      
    4-amidinopiperidinyl-                                                 
               methyl                                                     
                    n-butylsulfonyl                                       
                                 OMe                                      
    methyl                                                                
2167                                                                      
    4-amidinopiperidinyl-                                                 
               methyl                                                     
                    2-methylphenylsulfonyl                                
                                 OH                                       
    methyl                                                                
2168                                                                      
    4-amidinopiperidinyl-                                                 
               methyl                                                     
                    2-bromophenylsulfonyl                                 
                                 OH                                       
    methyl                                                                
2169                                                                      
    4-amidinopiperidinyl-                                                 
               methyl                                                     
                    3-methylphenylsulfonyl                                
                                 OH                                       
    methyl                                                                
2170                                                                      
    4-amidinopiperidinyl-                                                 
               methyl                                                     
                    3-methylphenylsulfonyl                                
                                 OMe                                      
    methyl                                                                
2171                                                                      
    4-amidinopiperidinyl-                                                 
               methyl                                                     
                    3,5-dimethylisoxazolyl                                
                                 OH                                       
    methyl          sulfonyl                                              
2172                                                                      
    4-amidinopiperidinyl-                                                 
               methyl                                                     
                    3,5-dimethylisoxazolyl                                
                                 OMe                                      
    methyl          sulfonyl                                              
2173                                                                      
    4-amidinopiperidinyl-                                                 
               methyl                                                     
                    styrylsulfonyl                                        
                                 OH                                       
    methyl                                                                
2174                                                                      
    4-amidinopiperidinyl-                                                 
               methyl                                                     
                    benzyloxycarbonyl                                     
                                 OH                                       
    methyl                                                                
2175                                                                      
    4-amidinopiperidinyl-                                                 
               methyl                                                     
                    benzyloxycarbonyl                                     
                                 OMe                                      
    methyl                                                                
2176                                                                      
    4-amidinopiperidinyl-                                                 
               methyl                                                     
                    n-butyloxycarbonyl                                    
                                 OH                                       
    methyl                                                                
2177                                                                      
    4-amidinopiperidinyl-                                                 
               methyl                                                     
                    n-butyloxycarbonyl                                    
                                 OMe                                      
    methyl                                                                
2178                                                                      
    4-amidinophenyl                                                       
               methyl                                                     
                    phenylcarbonyl                                        
                                 OMe                                      
2179                                                                      
    4-amidinophenyl                                                       
               methyl                                                     
                    phenylcarbonyl                                        
                                 OH                                       
2180                                                                      
    4-amidinophenyl                                                       
               methyl                                                     
                    2,6-methylphenylcarbonyl                              
                                 OMe                                      
2181                                                                      
    4-amidinophenyl                                                       
               methyl                                                     
                    2,6-methylphenylcarbonyl                              
                                 OH                                       
2182                                                                      
    4-amidinophenyl                                                       
               methyl                                                     
                    2-methylphenylcarbonyl                                
                                 OMe                                      
2183                                                                      
    4-amidinophenyl                                                       
               methyl                                                     
                    2-methylphenylcarbonyl                                
                                 OH                                       
2184                                                                      
    4-amidinophenyl                                                       
               methyl                                                     
                    2-bromophenylcarbonyl                                 
                                 OMe                                      
2185                                                                      
    4-amidinophenyl                                                       
               methyl                                                     
                    2-bromophenylcarbonyl                                 
                                 OH                                       
2186                                                                      
    4-amidinophenyl                                                       
               methyl                                                     
                    3-methylphenylcarbonyl                                
                                 OMe                                      
2187                                                                      
    4-amidinophenyl                                                       
               methyl                                                     
                    3-methylphenylcarbonyl                                
                                 OH                                       
2188                                                                      
    4-amidinophenyl                                                       
               methyl                                                     
                    3,5-dimethyl-                                         
                                 OMe                                      
                    isoxazoylcarbonyl                                     
2189                                                                      
    4-amidinophenyl                                                       
               methyl                                                     
                    3,5-dimethyl-                                         
                                 OH                                       
                    isoxazoylcarbonyl                                     
2190                                                                      
    4-piperidinylethyl                                                    
               methyl                                                     
                    phenylcarbonyl                                        
                                 OMe                                      
2191                                                                      
    4-piperidinylethyl                                                    
               methyl                                                     
                    phenylcarbonyl                                        
                                 OH                                       
2192                                                                      
    4-piperidinylethyl                                                    
               methyl                                                     
                    2,6-methylphenylcarbonyl                              
                                 OMe                                      
2193                                                                      
    4-piperidinylethyl                                                    
               methyl                                                     
                    2,6-methylphenylcarbonyl                              
                                 OH                                       
2194                                                                      
    4-piperidinylethyl                                                    
               methyl                                                     
                    2-methylphenylcarbonyl                                
                                 OMe                                      
2195                                                                      
    4-piperidinylethyl                                                    
               methyl                                                     
                    2-methylphenylcarbonyl                                
                                 OH                                       
2196                                                                      
    4-piperidinylethyl                                                    
               methyl                                                     
                    2-bromophenylcarbonyl                                 
                                 OMe                                      
2197                                                                      
    4-piperidinylethyl                                                    
               methyl                                                     
                    2-bromophenylcarbonyl                                 
                                 OH                                       
2198                                                                      
    4-piperidinylethyl                                                    
               methyl                                                     
                    3-methylphenylcarbonyl                                
                                 OMe                                      
2199                                                                      
    4-piperidinylethyl                                                    
               methyl                                                     
                    3-methylphenylcarbonyl                                
                                 OH                                       
2200                                                                      
    4-piperidinylethyl                                                    
               methyl                                                     
                    3,5-dimethyl-                                         
                                 OMe                                      
                    isoxazoylcarbonyl                                     
2201                                                                      
    4-piperidinylethyl                                                    
               methyl                                                     
                    3,5-dimethyl-                                         
                                 OH                                       
                    isoxazoylcarbonyl                                     
2202                                                                      
    4-piperidinylethyl                                                    
               methyl                                                     
                    n-butyloxycarbonyl                                    
                                 OH                                       
__________________________________________________________________________

                                  TABLE 11                                
__________________________________________________________________________
                                  (VI)                                    
 ##STR363##                                                               
Example                        MS                                         
Number                                                                    
     R.sup.2                                                              
           R.sup.8          Y  (M +  H).sup.+                             
__________________________________________________________________________
2220 H     CH.sub.2 NHCO.sub.2 n-C.sub.3 H.sub.7                          
                            OH                                            
2221 H     CH.sub.2 NHCO.sub.2 n-C.sub.4 H.sub.9                          
                            OH                                            
2222 H     CH.sub.2 NHCO.sub.2 n-C.sub.5 H.sub.11                         
                            OH                                            
2223 H     CH.sub.2 NHCO.sub.2 CH.sub.2 Ph                                
                            OH                                            
2224 H     CH.sub.2 NHCO.sub.2 CH.sub.2 CH.sub.2 Ph                       
                            OH                                            
2225 H     CH.sub.2 NHCO.sub.2 i-C.sub.4 H.sub.9                          
                            OH                                            
2226 H     CH.sub.2 NHSO.sub.2 CH.sub.2 Ph                                
                            OH                                            
2227 H                                                                    
            ##STR364##      OH                                            
2228 H                                                                    
            ##STR365##      OH                                            
2229 H                                                                    
            ##STR366##      OH                                            
2230 H                                                                    
            ##STR367##      OH                                            
2231 n-Bu  CH.sub.2 NHCO.sub.2 n-C.sub.3 H.sub.7                          
                            OH                                            
2232 n-Bu  CH.sub.2 NHCO.sub.2 n-C.sub.4 H.sub.9                          
                            OH                                            
2233 n-Bu  CH.sub.2 NHCO.sub.2 n-C.sub.5 H.sub.11                         
                            OH                                            
2234 n-Bu  CH.sub.2 NHCO.sub.2 CH.sub.2 Ph                                
                            OH                                            
2235 n-Bu  CH.sub.2 NHCO.sub.2 CH.sub.2 CH.sub.2 Ph                       
                            OH                                            
2236 n-Bu  CH.sub.2 NHCO.sub.2 i-C.sub.4 H.sub.9                          
                            OH                                            
2237 n-Bu  CH.sub.2 NHSO.sub.2 CH.sub.2 Ph                                
                            OH                                            
2238 n-Bu                                                                 
            ##STR368##      OH                                            
2239 n-Bu                                                                 
            ##STR369##      OH                                            
2240 n-Bu                                                                 
            ##STR370##      OH                                            
2241 n-Bu                                                                 
            ##STR371##      OH                                            
2242 o-methoxy-                                                           
           --CH.sub.2 CH.sub.3                                            
                            OH                                            
     benzyl                                                               
2243 o-methoxy-                                                           
           --CH═CH.sub.2                                              
                            OH                                            
     benzyl                                                               
2244 o-methoxy-                                                           
           --C.tbd.CH       OH                                            
     benzyl                                                               
2245 o-methoxy-                                                           
           CH.sub.2 NHCO.sub.2 n-C.sub.3 H.sub.7                          
                            OH                                            
     benzyl                                                               
2246 o-methoxy-                                                           
           CH.sub.2 NHCO.sub.2 n-C.sub.4 H.sub.9                          
                            OH                                            
     benzyl                                                               
2247 o-methoxy-                                                           
           CH.sub.2 NHCO.sub.2 n-C.sub.5 H.sub.11                         
                            OH                                            
     benzyl                                                               
2248 methoxy-                                                             
           CH.sub.2 NHCO.sub.2 CH.sub.2 Ph                                
                            OH                                            
     benzyl                                                               
2249 o-methoxy-                                                           
           CH.sub.2 NHCO.sub.2 CH.sub.2 CH.sub.2 Ph                       
                            OH                                            
     benzyl                                                               
2250 o-methoxy-                                                           
           CH.sub.2 NHCO.sub.2 i-C.sub.4 H.sub.9                          
                            OH                                            
     benzyl                                                               
2251 o-methoxy-                                                           
           CH.sub.2 NHSO.sub.2 CH.sub.2 Ph                                
                            OH                                            
     benzyl                                                               
2252 o-methoxy-  benzyl                                                   
            ##STR372##      OH                                            
2253 o-methoxy-  benzyl                                                   
            ##STR373##      OH                                            
2254 o-methoxy-  benzyl                                                   
            ##STR374##      OH                                            
2255 o-methoxy-  benzyl                                                   
            ##STR375##      OH                                            
2256 o-methoxy-                                                           
           --CH.sub.2 CH.sub.3                                            
                            OH                                            
     benzyl                                                               
2257 o-methoxy-                                                           
           --CH═CH.sub.2                                              
                            OH                                            
     benzyl                                                               
2258 o-methoxy-                                                           
           --C.tbd.CH       OH                                            
     benzyl                                                               
__________________________________________________________________________

              TABLE 12                                                    
______________________________________                                    
 ##STR376##                                                               
Ex.                                    MS                                 
No.  R.sup.1   R.sup.16      m    n    (M +  H).sup.+                     
______________________________________                                    
2280 guanidino benzyloxycarbonyl                                          
                             2    2    449                                
2281 guanidino benzyloxycarbonyl                                          
                             1    2    435                                
2282 guanidino benzyloxycarbonyl                                          
2283 guanidino benzyloxycarbonyl                                          
2284 guanidino benzyloxycarbonyl                                          
2285 guanidino benzyloxycarbonyl                                          
______________________________________                                    

              TABLE 13                                                    
______________________________________                                    
 ##STR377##                                                               
Ex.                                    MS                                 
No.  R.sup.1   R.sup.16      m    n    (M +  H).sup.+                     
______________________________________                                    
2400 guanidino benzyloxycarbonyl                                          
                             2    2    449                                
2401 guanidino benzyloxycarbonyl                                          
                             3    0    435                                
2402 guanidino benzyloxycarbonyl                                          
                             5    0    463                                
2403 guanidino benzyloxycarbonyl                                          
                             3    2    463                                
2404 guanidino benzyloxycarbonyl                                          
                             4    2    477                                
2405 guanidino benzyloxycarbonyl                                          
                             2    0    421                                
2406 guanidino benzyloxycarbonyl                                          
                             4    0    449                                
______________________________________                                    

              TABLE 14                                                    
______________________________________                                    
 ##STR378##                                                               
Ex                                    MS                                  
No.  R.sup.1 -V   R.sup.16       Y    (M + H).sup.+                       
______________________________________                                    
2420 4-piperidinylpropyl                                                  
                  n-butyloxycarbonyl                                      
                                 OMe  441                                 
2421 4-piperidinylpropyl                                                  
                  4-methylphenylsulfonyl                                  
                                 OMe  495                                 
2422 4-piperidinylpropyl                                                  
                  4-methylphenylsulfonyl                                  
                                 OH   481                                 
2423 4-piperidinylpropyl                                                  
                  n-butyloxycarbonyl                                      
                                 OH   427                                 
______________________________________
Utility
The compounds of this invention possess antiplatelet efficacy, as evidenced by their activity in standard platelet aggregation assays or platelet fibrinogen binding assays, as described below. A compound is considered to be active in these assays if it has an IC50 value of less than about 1 mM. Platelet aggregation and fibrinogen binding assays which may be used to demonstrate the antiplatelet activity of the compounds of the invention are described below.
Platelet Aggregation Assay: Venous blood was obtained from the arm of a healthy human donor who was drug-free and aspirin-free for at least two weeks prior to blood collection. Blood was collected into 10 mL citrated Vacutainer tubes. The blood was centrifuged for 15 minutes at 150×g at room temperature, and platelet-rich plasma (PRP) was removed. The remaining blood was centrifuged for 15 minutes at 1500×g at room temperature, and platelet-poor plasma (PPP) was removed. Samples were assayed on a aggregometer (PAP-4 Platelet Aggregation Profiler), using PPP as the blank (100% transmittance). 200 μL of PRP was added to each micro test tube, and transmittance was set to 0%. 20 μL of various agonists (ADP, collagen, arachidonate, epinephrine, thrombin) were added to each tube, and the aggregation profiles were plotted (% transmittance versus time). The results are expressed as % inhibition of agonist-induced platelet aggregation. For the IC50 evaluation, the test compounds were added at various concentrations prior to the activation of the platelets.
Ester prodrugs were preincubated (10-3 M F.C.) with 100 IU/mL Porcine liver esterase (Sigma Chemical Co., St. Louis, Mo., #E-3128) for 2 hours at 37° C. Aliquots are then diluted in 0.1 M Tris, pH 7.4, to the desired concentrations. Aliquots of 20 μl of the esterase pretreated prodrugs are added to 200 μl of human platelet rich plasma. Samples were placed in platelet profiler (aggregometer) for 8 minutes at 37° C., followed by the addition of 100 μM Adenosine Diphosphate, (Sigma Chemical Co., St. Louis, Mo., #A-6521), to induce platelet aggregation. Platelet aggregation was allowed to proceed for 5 minutes. Percent inhibition is calculated using percent aggregation in the presence of the test compound divided by percent aggregation of control, times 100. This value is subtracted from 100, yielding percent inhibition. Calculation of IC50 is performed on a Texas Instruments TI59 with an IC50 program.
Purified GPIIb/IIIa-Fibrinogen Binding ELISA
The following reagents are used in the GPIIb/IIIa-fibrinogen binding ELISA:
purified GPIIb/IIIa (148.8 μg/mL);
biotinylated fibrinogen (˜1 mg/mL or 3000 nM);
anti-biotin alkaline phosphatase conjugate (Sigma no. A7418);
flat-bottom, high binding, 96-well plates (Costar Cat. no. 3590);
phosphatase substrate (Sigma 104) (40 mg capsules);
bovine serum albumin (BSA) (Sigma no. A3294);
Alkaline Phosphatase buffer-0.1 M glycine-HCl, 1 mM MgCl2.6H2 O, 1 mM ZnCl2, pH 10.4;
Binding buffer-20 mM Tris-HCl, 150 mM NaCl, 1 mM CaCl2.2H2 O, 0.02% NaN3, pH 7.0;
Buffer A-50 mM Tris-HCl, 100 mM NaCl, 2 mM CaCl2.2H2 O, 0.02% NaN3, pH 7.4;
Buffer A+3.5% BSA (Blocking buffer);
Buffer A+0.1% BSA (Dilution buffer); 2N NaOH.
The following method steps are used in the GPIIb/IIIa-fibrinogen binding ELISA:
Coat plates with GPIIb/IIIa in Binding buffer (125 ng/100 μL/well) overnight at 4° C. (Leave first column uncoated for non-specific binding). Cover and freeze plates at -70° C. until used. Thaw plate 1 hour at room temperature or overnight at 4° C. Discard coating solution and wash once with 200 μL Binding buffer per well. Block plate 2 hours at room temperature on shaker with 200 μL Buffer A+3.5% BSA (Blocking buffer) per well. Discard Blocking buffer and wash once with 200 μL Buffer A+0.1% BSA (Dilution buffer) per well. Pipet 11 μL of test compound (10× the concentration to be tested in Dilution buffer) into duplicate wells. Pipet 11 μL Dilution buffer into non-specific and total binding wells. Add 100 μL Biotinylated fibrinogen (1/133 in Dilution buffer, final concentration=20 nM) to each well. Incubate plates for 3 hours at room temperature on a plate shaker. Discard assay solution and wash twice with 300 μL Binding buffer per well. Add 100 μL Anti-biotin alkaline phosphatase conjugate (1/1500 in Dilution buffer) to each well. Incubate plates for 1 hour at room temperature on plate shaker. Discard conjugate and wash twice with 300 51 Binding buffer per well. Add 100 μL Phosphatase substrate (1.5 mg/mL in Alkaline phosphatase buffer) to each well. Incubate plate at room temperature on shaker until color develops. Stop color development by adding 25 μL 2N NaOH per well. Read plate at 405 nm. Blank against non-specific binding (NSB) well. % Inhibition is calculated as
100-(Test Compound Abs/Total Abs)×100.
Platelet-Fibrinogen Binding Assay: Binding of 125 I-fibrinogen to platelets was performed as described by Bennett et al. (1983) Proc. Natl. Acad. Sci. USA 80: 2417-2422, with some modifications as described below. Human PRP (h-PRP) was applied to a Sepharose column for the purification of platelet fractions. Aliquots of platelets (5×108 cells) along with 1 mM calcium chloride were added to removable 96 well plates prior to the activation of the human gel purified platelets (h-GPP). Activation of the human gel purified platelets was achieved using ADP, collagen, arachidonate, epinephrine, and/or thrombin in the presence of the ligand, 125 I-fibrinogen. The 125 I-fibrinogen bound to the activated platelets was separated from the free form by centrifugation and then counted on a gamma counter. For an IC50 evaluation, the test compounds were added at various concentrations prior to the activation of the platelets.
The compounds of Formula I of the present invention may also possess thrombolytic efficacy, that is, they are capable of lysing (breaking up) already formed platelet-rich fibrin blood clots, and thus are useful in treating a thrombus formation, as evidenced by their activity in the tests described below. Preferred compounds of the present invention for use in thrombolysis include those compounds having an IC50 value (that is, the molar concentration of the compound capable of achieving 50% clot lysis) of less than about 1 μM, more preferably an IC50 value of less than about 0.1 μM.
Thrombolytic Assay: Venous blood was obtained from the arm of a healthy human donor who was drug-free and aspirin free for at least two weeks prior to blood collection, and placed into 10 ml citrated Vacutainer tubes. The blood was centrifuged for 15 minutes at 1500×g at room temperature, and platelet rich plasma (PRP) was removed. To the PRP was then added 1×10-3 M of the agonist ADP, epinephrine, collagen, arachidonate, serotonin or thrombin, or a mixture thereof, and the PRP incubated for 30 minutes. The PRP was centrifuged for 12 minutes at 2500×g at room temperature. The supernatant was then poured off, and the platelets remaining in the test tube were resuspended in platelet poor plasma (PPP), which served as a plasminogen source. The suspension was then assayed on a Coulter Counter (Coulter Electronics, Inc., Hialeah, Fla.), to determine the platelet count at the zero time point. After obtaining the zero time point, test compounds were added at various concentrations. Test samples were taken at various time points and the platelets were counted using the Coulter Counter. To determine the percent of lysis, the platelet count at a time point subsequent to the addition of the test compound was subtracted from the platelet count at the zero time point, and the resulting number divided by the platelet count at the zero time point. Multiplying this result by 100 yielded the percentage of clot lysis achieved by the test compound. For the IC50 evaluation, the test compounds were added at various concentrations, and the percentage of lysis caused by the test compounds was calculated.
The compounds of Formula I of the present invention are also useful for administration in combination with anti-coagulant agents such as warfarin or heparin, or antiplatelet agents such as aspirin, piroxicam or ticlopidine, or thrombin inhibitors such as boropeptides, hirudin or argatroban, or thrombolytic agents such as tissue plasminogen activator, anistreplase, urokinase or streptokinase, or combinations thereof.
The compounds of Formula I of the present invention may also be useful as antagonists of other integrins such as for example, the αv /β3 or vitronectin receptor, α4 /β1 or α5 /β1 and as such may also have utility in the treatment and diagnosis of osteoporosis, cancer metastasis, diabetic retinopathy, rheumatoid arthritis, inflammation, and autoimmune disorders. The compounds of Formula I of the present invention may be useful for the treatment or prevention of other diseases which involve cell adhesion processes, including, but not limited to, inflammation, bone degradation, rheumatoid arthritis, asthma, allergies, adult respiratory distress syndrome, graft versus host disease, organ transplantation, septic shock, psoriasis, eczema, contact dermatitis, osteoporosis, osteoarthritis, atherosclerosis, metastasis, wound healing, diabetic retinopathy, inflammatory bowel disease and other autoimmune diseases.
Table A below sets forth the antiplatelet activity of representative compounds of the present invention. The indicated compounds were tested for their ability to inhibit platelet aggregation (using platelet rich plasma (PRP)). The IC50 value (the concentration of antagonist which inhibits platelet aggregation by 50% relative to a control lacking the antagonist) is shown. In Table 5 the IC50 values are expressed as: +++=IC50 of <10 μM; ++=IC50 of 10-50 μM; +=IC50 of 50-100 μM (μM=micromolar).
              TABLE A                                                     
______________________________________                                    
              Platelet     Platelet                                       
              Aggregation Assay                                           
                           Aggregation Assay                              
              IC.sub.50 (without                                          
                           IC.sub.50 (with                                
Example Number                                                            
              esterase)    esterage)                                      
______________________________________                                    
  1           +++                                                         
  4 (isomer A)                                                            
              ++                                                          
  4 (isomer B)                                                            
              ++                                                          
  7           >100                                                        
  8           +                                                           
  9 (isomer A)                                                            
              +++                                                         
  9 (isomer B)                                                            
              +++                                                         
 33           >100                                                        
 43           +++                                                         
 89                        +++                                            
 115                       +++                                            
 119A (3R)                 +++                                            
 119B (3S)                 +++                                            
 120A (3R)                 +++                                            
 120B (3S)                 +++                                            
 120C (3R)†† +++                                            
 166                       +++                                            
 189          >100                                                        
 190          +                                                           
 275                       +++                                            
 276                       +++                                            
 278                       +++                                            
 290                       +++                                            
 300                       +++                                            
 312                       +++                                            
 314A (2S)†         +++                                            
 314B (2S)†† +++                                            
 323                       +++                                            
 324                       +++                                            
 326                       +++                                            
 327 (2S)                  +++                                            
 328 (2S)                  +++                                            
 338 (3S)     +            +++                                            
 339 (3S)     +++                                                         
 340 (3S)     +            ++                                             
 341 (3S)     +++                                                         
 342 (2S)     +++                                                         
 344 (3R)                  +++                                            
 345                       +++                                            
 347 (3R)††  +++                                            
 348 (3R)                  +++                                            
 350                       +++                                            
 359                       +++                                            
 362                       +++                                            
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 368                       +++                                            
 373          ++                                                          
 371A                      +++                                            
 371B                      +++                                            
 374 (2S)     +            +++                                            
 375*         +++                                                         
 377          +++                                                         
 394                       +++                                            
 394Aft                    +++                                            
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 441          +++                                                         
 442                       +++                                            
 443 (2S)                  +++                                            
 444 (2S)                  +++                                            
 445 (2S)                  +++                                            
 446                       +++                                            
 449A                      +++                                            
 449B                      +++                                            
 450                       +++                                            
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 457                       +++                                            
 458A         +++                                                         
 458B         +++                                                         
 460A         +++                                                         
 460B         +++                                                         
 462                       +++                                            
 463          +++                                                         
 464                       +++                                            
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 466                       +++                                            
 467                       +++                                            
 468                       +++                                            
 469                       +++                                            
 470                       +++                                            
 471                       +++                                            
 472                       +++                                            
 473A (2S)†         +++                                            
 473B (2S)†† +++                                            
 474                       +++                                            
 475                       +++                                            
 476                       +++                                            
 477                       +++                                            
 478                       +++                                            
 479                       +++                                            
 480                       +++                                            
 481                       +++                                            
 482                       +++                                            
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 485                       +++                                            
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 492                       +++                                            
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 494                       +++                                            
 495                       +++                                            
 596                       +++                                            
 504                       +++                                            
 505                       +++                                            
 506                       +++                                            
 507                       +++                                            
 508                       +++                                            
 509                       +++                                            
 510                       +++                                            
 511                       +++                                            
 512                       +++                                            
 513                       +++                                            
 514                       +++                                            
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 516                       +++                                            
 517                       +++                                            
 518                       +++                                            
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 520                       +++                                            
 522                       +++                                            
 523                       +++                                            
 524                       +++                                            
 525                       +++                                            
 526          +++                                                         
 527                       +++                                            
 528          +++                                                         
 529                       +++                                            
 530          +++                                                         
 531                       +++                                            
 532          +++                                                         
 533                       +++                                            
 534          +++                                                         
 535                       +++                                            
 536          +++                                                         
 537                       +++                                            
 538          +++                                                         
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 587A (2S)††                                                
              +++                                                         
 588                       +++                                            
 602                       +++                                            
 611                       +++                                            
 612                       +++                                            
 613                       +++                                            
 616          +++                                                         
 642                       +++                                            
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 727                       +++                                            
 729                       +++                                            
 798                       +++                                            
 829                       +++                                            
1284                       +++                                            
1321                       +++                                            
1525                       +++                                            
1694                       +++                                            
1731                       +++                                            
2104                       +++                                            
2109                       +++                                            
2110                       +++                                            
2111                       +++                                            
2112                       +++                                            
2113                       +++                                            
2114                       +++                                            
2115                       +++                                            
2116                       +++                                            
2117                       +++                                            
2118                       +++                                            
2119                       +++                                            
2120                       +++                                            
2280                       +++                                            
2281                       +++                                            
2400                       +++                                            
2401                       +++                                            
2402                       +++                                            
2403                       +++                                            
2404                       +++                                            
2405                       +++                                            
2406                       +++                                            
______________________________________                                    
 * Single diastereomer, racemic                                           
 f S isomer at C5 of isoxazoline ring                                     
 ††R isomer at C5 of isoxazoline ring
The compounds of the present invention may be useful for the treatment or prevention of other diseases which involve cell adhesion processes, including, but not limited to, inflammation, bone degradation, thrombosis, rheumatoid arthritis, asthma, allergies, adult respiratory distress syndrome, graft versus host disease, organ transplantation, septic shock, psoriasis, eczema, contact dermatitis, osteoarthritis, atherosclerosis, metastasis, wound healing, diabetic retinopathy, inflammatory bowel disease and other angiogenic disorders.
The compounds of the formulae (Ie) and (If) possess selectivity as antagonists of integrins such as the αv /β3 vitronectin receptor. ##STR379##
The integrin antagonist activity of the compounds of the present invention is demonstrated using assays which measure the binding of a specific integrin to a native ligand, for example, using the ELISA assay described below for the binding of vitronectin to the αv /β3 receptor. The compounds provided by this invention are also useful as standards and reagents in determining the ability of a potential pharmaceutical to inhibit integrin-ligand binding. These would be provided in commercial kits comprising a compound of this invention.
Purified αv /β3 (human placenta)--Vitronectin ELISA:
The αv /β3 receptor was isolated from human placental extracts prepared using octylglucoside. The extracts were passed over an affinity column composed of anti-αv /β3 monoclonal antibody (LM609) to Affigel. The column was subsequently washed extensively at pH 7 and pH 4.5 followed by elution at pH 3. The resulting sample was concentrated by wheat germ agglutinin chromatography to provide gave two bands on SDS gel which were confirmed as αv /β3 by western blotting.
Affinity purified protein was diluted at different levels and plated to 96 well plates. ELISA was performed using fixed concentration of biotinylated vitronectin (approximately 80 nM/well). This receptor preparation contains the αv /β3 with no detectable levels of αv /β5 according to the gel (αv /β3) and according to effects of blocking antibodies for the αv /β3 or αv /β5 in the ELISA.
A submaximal concentration of biotinylated vitronectin was selected based on conc. response curve with fixed receptor conc. and variable concentrations of biotinylated vitronectin.
αv /β3 -Vitronectin Binding Assay
The purified receptor is diluted with coating buffer (20 mM Tris HCl, 150 mM NaCl, 2.0 mM CaCl2, 1.0 mM MgCl2.6H2 O, 1.0 mM MnCl2.4H2 O) and coated (100 μl/well) on Costar (3590) high capacity binding plates overnight at 4° C. The coating solution is discarded and the plates washed once with blocking/binding buffer (B/B buffer, 50 mM Tris HCl, 100 mM NaCl, 2.0 mM CaCl2, 1.0 mM MgCl2.6H2 O,1.0 mM MnCl2.4H2 O). Receptor is then blocked (200 μl/well) with 3.5% BSA in B/B buffer for 2 hours at room temperature. After washing once with 1.0% BSA in B/B buffer, biotinylated vitronectin (100 μl) and either inhibitor (11 μl) or B/B buffer w/1.0% BSA (11 μl) is added to each well. The plates are incubated 2 hours at room temperature. The plates are washed twice with B/B buffer and incubated 1 hour at room temperature with anti-biotin alkaline phosphatase (100 μl/well) in B/B buffer containing 1.0% BSA. The plates are washed twice with B/B buffer and alkaline phosphatase substrate (100 μl) is added. Color is developed at room temperature. Color development is stopped by addition of 2N NaOH (25 μl/well) and absorbance is read at 405 nm. The IC50 is the concentration of test substance needed to block 50% of the vitronectin binding to the receptor.
Integrin Cell-Based Adhesion Assays
In the adhesion assays, a 96 well plate was coated with the ligand (i.e., fibrinogen) and incubated overnight at 4° C. The following day, the cells were harvested, washed and loaded with a fluorescent dye. Compounds and cells were added together and then were immediately added to the coated plate. After incubation, loose cells are removed from the plate, and the plate (with adherent cells) is counted on a fluorometer. The ability of test compounds to inhibit cell adhesion by 50% is given by the IC50 value and represents a measure of potency of inhibition of integrin mediated binding. Compounds were tested for their ability to block cell adhesion using assays specific for αv /β3, αv /β5 and α5 /β1 integrin interactions.
Dosage and Formulation
The compounds of the present invention can be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. Likewise, they may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts. An effective but non-toxic amount of the compound desired can be employed as an anti-aggregation agent. Finally, the compounds of the invention may also be administered intranasally.
The compounds of this invention can be administered by any means that produces contact of the active agent with the agent's site of action, glycoprotein IIb/IIIa (GPIIb/IIIa), in the body of a mammal. They can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents, such as a second antiplatelet agent such as aspirin or ticlopidine which are agonist-specific. They can be administered alone, but generally administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
The dosage regimen for the compounds of the present invention will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the effect desired. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition.
By way of general guidance, the daily oral dosage of each active ingredient, when used for the indicated effects, will range between about 0.001 to 1000 mg/kg of body weight, preferably between about 0.01 to 100 mg/kg of body weight per day, and most preferably between about 1.0 to 20 mg/kg/day. Intravenously, the most preferred doses will range from about 1 to about 10 mg/kg/minute during a constant rate infusion. Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily.
The compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches wall known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
We have unexpectedly found that delivery of Example 327 (and it's free acid Example 300) through the nasal route provided very high bioactivity (inhibition of platelet aggregation) that was similar to that observed after administering the same dose intravenously. Also dog to dog variability was very small. For example, nasal and i.v. administration of 0.025 mg/kg gave similar profiles of platelet aggregation inhibition, however comparable effect after oral administration was only seen at doses equal or greater than 0.4 mg/kg. Therefore, the advantages of delivering Example 327 nasally are to enhance bioavailability and reduce variability. The latter is very important due to the steep dose response of these types of compounds.
The active ingredient can be administered intranasally to a mammal at a dosage range of about 0.01 to 0.5 mg/kg while the preferred dosage range is about 0.01-0.1 mg/kg.
Compositions of the active ingredients can be administered intranasally by preparing a suitable formulation of the active ingredient by procedures well known to those skilled in the art. Preferably the formulations are prepared with suitable nontoxic pharmaceutically acceptable ingredients. These ingredients are known to those skilled in the preparation of nasal dosage forms and some of these can be found in REMINGTON'S PHARMACEUTICAL SCIENCES. 17th edition, 1985 a standard reference in the field. The choice of suitable carriers is highly dependent upon the exact nature of the nasal dosage form desired, e.g., solutions, suspensions, ointments, or gels. Nasal dosage forms generally contain large amounts of water in addition to the active ingredient. Minor amounts of other ingredients such as pH adjusters, emulsifiers or dispersing agents, preservatives, surfactants, jelling agents, or buffering and other stabilizing and solubilizing agents may also be present. Preferably, the nasal dosage form should be isotonic with nasal secretions.
An example of a nasal solution composition of this invention includes:
______________________________________                                    
Active Drug           0.2-2 g                                             
Sorbitol              0.6 g                                               
Benzalkonium chloride 0.002 g                                             
Hydrochloric acid     to adjust pH                                        
Sodium hydroxide      to adjust pH                                        
Purified water        to 10 mL                                            
______________________________________
In this example the active drug can be in one vial and the rest of the formulation can be in another vial. The drug can be reconstituted when needed.
The formulation of this invention may be varied to include: (1) other acids and bases to adjust the pH; (2) other tonicity imparting agents such as glycerin and dextrose; (3) other antimicrobial preservatives such as other parahydroxy benzoic acid esters, sorbate, benzoate, propionate, chlorbutanol, phenylethyl alcohol, and mercurials; (4) other viscosity imparting agents such as sodium carboxy-methylcellulose microcrystalline cellulose, polyvinyl-pyrrolidone, polyvinyl alcohol and other gums; (5) suitable absorption enhancers; (6) stabilizing agents such as antioxidants, like bisulfite and ascorbate, metal chelating agents such as sodium edetate and drug solubility enhancers such as polyethylene glycols.
The above formulation can be administered as drops, sprays, aerosols or by any other intranasal dosage form. Optionally, the delivery system can be a unit dose delivery system. The volume of solution or suspension delivered per dose can be anywhere from 5 to 400 μL, and preferably between 50 and 150 μL. Delivery systems for these various dosage forms can be dropper bottles, plastic squeeze units, atomizers, nebulizers or pharmaceutical aerosols in either unit dose or multiple dose packages.
In the methods of the present invention, the compounds herein described in detail can form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as carrier materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.
For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl callulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamallar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.
Compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels.
Dosage forms (pharmaceutical compositions) suitable for administration may contain from about 1 milligram to about 100 milligrams of active ingredient per dosage unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.5-95% by weight based on the total weight of the composition.
The active ingredient can be administered orally in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups, and suspensions. It can also be administered parenterally, in sterile liquid dosage forms.
Gelatin capsules may contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.
In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.
Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field.
Representative useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows:
Capsules
A large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each with 1-20 milligrams of powdered active ingredient, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams magnesium stearate.
Soft Gelatin Capsules
A mixture of active ingredient in a digestable oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 1-20 milligrams of the active ingredient. The capsules are washed and dried.
Tablets
A large number of tablets are prepared by conventional procedures so that the dosage unit was 1-20 milligrams of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.8 milligrams of lactose. Appropriate coatings may be applied to increase palatability or delay absorption.
Injectable
A parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol and water. The solution is made isotonic with sodium chloride and sterilized.
Suspension
An aqueous suspension is prepared for oral administration so that each 5 mL contain 1-20 mg of finely divided active ingredient, 200 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, U.S.P., and 0.025 mL of vanillin.
The compounds of the present invention may be administered in combination with a second therapeutic agent selected from: an anti-coagulant agent such as warfarin or heparin; an anti-platelet agent such as aspirin, piroxicam or ticlopidine; a thrombin inhibitor such as a boropeptide thrombin inhibitor, or hirudin; or a thrombolytic agent such as plasminogen activators, such as tissue plasminogen activator, anistreplase, urokinase or streptokinase. The compound of Formula I and such second therapeutic agent can be administered separately or as a physical combination in a single dosage unit, in any dosage form and by various routes of administration, as described above.
The compound of Formula I may be formulated together with the second therapeutic agent in a single dosage unit (that is, combined together in one capsule, tablet, powder, or liquid, etc.). When the compound of Formula I and the second therapeutic agent are not formulated together in a single dosage unit, the compound of Formula I and the second therapeutic agent (anti-coagulant agent, anti-platelet agent, thrombin inhibitor, and/or thrombolytic agent) may be administered essentially at the same time, or in any order; for example the compound of Formula I may be administered first, followed by administration of the second agent (anti-coagulant agent, anti-platelet agent, thrombin inhibitor, and/or thrombolytic agent). When not administered at the same time, preferably the administration of the compound of Formula I and the second therapeutic agent occurs less than about one hour apart.
A preferable route of administration of the compound of Formula I is oral. Although it is preferable that the compound of Formula I and the second therapeutic agent (anti-coagulant agent, anti-platelet agent, thrombin inhibitor, and/or thrombolytic agent) are both administered by the same route (that is, for example, both orally), if desired, they may each be administered by different routes and in different dosage forms (that is, for example, one component of the combination product may be administered orally, and another component may be administered intravenously).
The dosage of the compound of Formula I when administered alone or in combination with a second therapeutic agent may vary depending upon various factors such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration, the age, health and weight of the recipient, the nature and extent of the symptoms, the kind of concurrent treatment, the frequency of treatment, and the effect desired, as described above.
Although the proper dosage of the compound of Formula I when administered in combination with the second therapeutic agent will be readily ascertainable by a medical practitioner skilled in the art, once armed with the present disclosure, by way of general guidance, where the compounds of this invention are combined with anti-coagulant agents, for example, a daily dosage may be about 0.1 to 100 milligrams of the compound of Formula I and about 1 to 7.5 milligrams of the anti-coagulant, per kilogram of patient body weight. For a tablet dosage form, the novel compounds of this invention generally may be present in an amount of about 1 to 10 milligrams per dosage unit, and the anti-coagulant in an amount of about 1 to 5 milligrams per dosage unit.
Where the compounds of Formula I are administered in combination with a second anti-platelet agent, by way of general guidance, typically a daily dosage may be about 0.01 to 25 milligrams of the compound of Formula I and about 50 to 150 milligrams of the additional anti-platelet agent, preferably about 0.1 to 1 milligrams of the compound of Formula I and about 1 to 3 milligrams of antiplatelet agents, per kilogram of patient body weight.
Further, by way of general guidance, where the compounds of Formula I are adminstered in combination with thrombolytic agent, typically a daily dosage may be about 0.1 to 1 milligrams of the compound of Formula I, per kilogram of patient body weight and, in the case of the thrombolytic agents, the usual dosage of the thrombolyic agent when administered alone may be reduced by about 70-80% when administered with a compound of Formula I.
Where two or more of the foregoing second therapeutic agents are administered with the compound of formula I, generally the amount of each component in a typical daily dosage and typical dosage form may be reduced relative to the usual dosage of the agent when administered alone, in view of the additive or synergistic effect of the therapeutic agents when administered in combination.
Particularly when provided as a single dosage unit, the potential exists for a chemical interaction between the combined active ingredients. For this reason, when the compound of Formula I and a second therapeutic agent are combined in a single dosage unit they are formulated such that although the active ingredients are combined in a single dosage unit, the physical contact between the active ingredients is minimized (that is, reduced) For example, one active ingredient may be enteric coated. By enteric coating one of the active ingredients, it is possible not only to minimize the contact between the combined active ingredients, but also, it is possible to control the release of one of these components in the gastrointestinal tract such that one of these components is not released in the stomach but rather is released in the intestines. One of the active ingredients may also be coated with a sustained-release material which effects a sustained-release throughout the gastrointestinal tract and also serves to minimize physical contact between the combined active ingredients. Furthermore, the sustained-released component can be additionally enteric coated such that the release of this component occurs only in the intestine. Still another approach would involve the formulation of a combination product in which the one component is coated with a sustained and/or enteric release polymer, and the other component is also coated with a polymer such as a lowviscosity grade of hydroxypropyl methylcellulose (HPMC) or other appropriate materials as known in the art, in order to further separate the active components. The polymer coating serves to form an additional barrier to interaction with the other component.
These as well as other ways of minimizing contact between the components of combination products of the present invention, whether administered in a single dosage form or administered in separate forms but at the same time by the same manner, will be readily apparent to those skilled in the art, once armed with the present disclosure.
The present invention also includes pharmaceutical kits useful, for example, in the inhibition of platelet aggregation, the treatment of blood clots, and/or the treatment of thromboembolic disorders, which comprise one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I. Such kits may further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, may also be included in the kit.
In the present disclosure it should be understood that the specified materials and conditions are important in practicing the invention but that unspecified materials and conditions are not excluded so long as they do not prevent the benefits of the invention from being realized.

Claims (49)

What is claimed is:
1. A compound of Formula I: ##STR380## or pharmaceutically acceptable salt form thereof wherein: b is a carbon-carbon single or double bond;
R1 is selected from R2 (R3)N(CH2)q Z--, R2 (R3)N(R2 N═)CN(R2)(CH2)q Z--, piperazinyl--(CH2)q Z-- or ##STR381## Z is selected from O, S, S(═O), or S(═O)2 ; R2 and R3 are independently selected from: H, C1 -C10 alkyl, C2 -C6 alkenyl, C3 -C11 cycloalkyl, C4 -C11 cycloalkylalkyl, C6 -C10 aryl, C7 -C11 arylalkyl, C2 -C7 alkylcarbonyl, C6 -C10 arylcarbonyl, C2 -C10 alkoxycarbonyl, C4 -C11 cycloalkoxycarbonyl, C7 -C11 bicycloalkoxycarbonyl, C6 -C10 aryloxycarbonyl, aryl(C1 -C10 alkoxy)carbonyl, C1 -C6 alkylcarbonyloxy(C1 -C4 alkoxy)carbonyl, C6 -C10 arylcarbonyloxy(C1 -C4 alkoxy)carbonyl, C4 -C11 cycloalkylcarbonyloxy(C1 -C4 alkoxy)carbonyl;
U is selected from:
a single bond,
--(C1 -C7 alkyl)--,
--(C2 -C7 alkenyl)--,
--(C2 -C7 alkynyl)--,
--(aryl)--substituted with 0-3 R6a, or
--(pyridyl)--substituted with 0-3 R6a ;
V is selected from:
a single bond;
--(C1 -C7 alkyl)--, substituted with 0-3 groups independently selected from R6 or R7 ;
--(C2 -C7 alkenyl)--, substituted with 0-3 groups independently selected from R6 or R7 ;
--(C2 -C7 alkynyl)--, substituted with 0-2 groups independently selected from R6 or R7 ;
-(aryl)-, substituted with 0-2 groups independently selected from R6 or R7 ;
-(pyridyl)-, substituted with 0-2 groups independently selected from R6 or R7 ; or
-(pyridazinyl)-, substituted with 0-2 groups independently selected from R6 or R7 ;
W is selected from:
a single bond,
--(C1 -C7 alkyl)-,
--(C2 -C7 alkenyl)-,
--(C2 -C7 alkynyl)-, or
--(C(R5)2)n C(═O) N(R5a)--;
X is selected from:
a single bond;
--(C1 -C7 alkyl)-, substituted with 0-3 groups independently selected from R4, R8 or R14 ;
--(C2 -C7 alkenyl)-, substituted with 0-3 groups independently selected from R4, R8 or R14 ;
--(C2 -C7 alkynyl)-, substituted with 0-2 groups independently selected from R4, R8 or R14 ; or ##STR382## Y is selected from hydroxy, C1 to C10 alkyloxy, C3 to C11 cycloalkyloxy, C6 to C10 aryloxy, C7 to C11 aralkyloxy, C3 to C10 alkylcarbonyloxyalkyloxy, C3 to C10 alkoxycarbonyloxyalkyloxy, C2 to C10 alkoxycarbonylalkyloxy, C5 to C10 cycloalkylcarbonyloxyalkyloxy, C5 to C10 cycloalkoxycarbonyloxyalkyloxy, C5 to C10 cycloalkoxycarbonylalkyloxy, C7 to C11 aryloxycarbonylalkyloxy, C8 to C12 aryloxycarbonyloxyalkyloxy, C8 to C12 arylcarbonyloxyalkyloxy, C5 to C10 alkoxyalkylcarbonyloxyalkyloxy, C5 to C10 (5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, C10 to C14 (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy; or (R2)(R3)N--(C1 -C10 alkoxy)-;
R4 and R4b are independently selected from H, C1 -C10 alkyl, hydroxy, C1 -C10 alkoxy, nitro, C1 -C10 alkylcarbonyl, or --N(R12)R13 ;
R5 is selected from H, C1 -C8 alkyl, C2 -C6 alkenyl, C3 -C11 cycloalkyl, C4 -C11 cycloalkylmethyl, C6 -C10 aryl, C7 -C11 arylalkyl, or C1 -C10 alkyl substituted with 0-2 R4b ;
R5a is selected from hydrogen, hydroxy, C1 to C8 alkyl, C2 to C6 alkenyl, C3 to C11 cycloalkyl, C4 to C11 cycloalkylmethyl, C1 -C6 alkoxy, benzyloxy, C6 to C10 aryl, heteroaryl, heteroarylalkyl, C7 to C11 arylalkyl, adamantylmethyl or C1 -C10 alkyl substituted with 0-2 R4b ;
alternately, R5 and R5 a can be taken together to be 3-azabicyclononyl, 1-piperidinyl, 1-morpholinyl or 1-piperazinyl, each being optionally substituted with C1 -C6 alkyl, C6 -C10 aryl, heteroaryl, C7 -C11 arylalkyl, C1 -C6 alkylcarbonyl, C3 -C7 cycloalkylcarbonyl, C1 -C6 alkoxycarbonyl, C7 -C11 arylalkoxycarbonyl, C1 -C6 alkylsulfonyl or C6 -C10 arylsulfonyl;
R5b is selected from C1 -C8 alkyl, C2 -C6 alkenyl, C3 -C11 cycloalkyl, C4 -C11 cycloalkylmethyl, C6 -C10 aryl, C7 -C11 arylalkyl, or C1 -C10 alkyl substituted with 0-2 R4b ;
R6 is selected from H, C1 -C10 alkyl, hydroxy, C1 -C10 alkoxy, nitro, C1 -C10 alkylcarbonyl, --N(R12)R13, cyano, halo, CF3, CHO, CO2 R5, C(═O)R5a, CONR5 R5a, OC(═O)R5a, OC(═O)OR5b, OR5a, OC(═O)NR5 R5a, OCH2 CO2 R5, CO2 CH2 CO2 R5, NO2, NR5a C(═O)R5a, NR5a C(═O)OR5b, NR5a C(═O) NR5 R5a, NR5a SO2 NR5 R5a, NR5a SO2 R5, S(O)p R5a, SO2 NR5 R5a, C2 to C6 alkenyl, C3 to C11 cycloalkyl, C4 to C11 cycloalkylmethyl;
C6 to C10 aryl optionally substituted with 1-3 groups selected from halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m Me, or --NMe2 ;
C7 to C11 arylalkyl, said aryl being optionally substituted with 1-3 groups selected from halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m Me, or --NMe2 ; methylenedioxy when R6 is a substituent on aryl; or
a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R7 ;
R6a is selected from C1 -C4 alkyl, C1 -C4 alkoxy, halo, CF3, NO2, or NR12 R13 ;
R7 is selected from H, C1 -C10 alkyl, hydroxy, C1 -C10 alkoxy, nitro, C1 -C10 alkylcarbonyl, --N(R12)R13, cyano, halo, CF3, CHO, CO2 R5, C(═O)R5a, CONR5 R5a, OC(═O)R5a, OC(═O)OR5b, OR5a, OC(═O)NR5 R5a, OCH2 CO2 R5, CO2 CH2 CO2 R5, NO2, NR5a C(═O)R5a, NR5a C(═O)OR5b, NR5a C(═O)NR5 R5a, NR5a SO2 NR5 R5a, NR5a SO2 R5, S(O)p R5a, SO2 NR5 R5a, C2 to C6 alkenyl, C3 to C11 cycloalkyl, C4 to C11 cycloalkylmethyl, C6 to C10 aryl, or C7 to C11 arylalkyl;
R8 is selected from:
H;
R6 ;
C1 -C10 alkyl, substituted with 0-3 R6 ;
C2 -C10 alkenyl, substituted with 0-3 R6 ;
C2 -C10 alkynyl, substituted with 0-3 R6 ;
C3 -C8 cycloalkyl, substituted with 0-3 R6 ;
C5 -C6 cycloalkenyl, substituted with 0-2 R6 ;
aryl, substituted with 0-2 R6 ;
- 10membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R6 ;
R12 and R13 are independently H, C1 -C10 alkyl, C1 -C10 alkoxycarbonyl, C1 -C10 alkylcarbonyl, C1 -C10 alkylsulfonyl, aryl(C1 -C10 alkyl)sulfonyl, arylsulfonyl, aryl, C2 -C6 alkenyl, C3 -C11 cycloalkyl, C4 -C11 cycloalkylalkyl, C7 -C11 arylalkyl, C2 -C7 alkylcarbonyl, C7 -C11 arylcarbonyl, C2 -C10 alkoxycarbonyl, C4 -C11 cycloalkoxycarbonyl, C7 -C11 bicycloalkoxycarbonyl, C7 -C11 aryloxycarbonyl, heteroarylcarbonyl, heteroarylsulfonyl, heteroarylalkylcarbonyl or aryl(C1 -C10 alkoxy)carbonyl;
R14 is selected from H, C1 -C10 alkyl, C2 -C10 alkenyl, C2 -C10 alkynyl, C1 -C10 alkoxy, aryl, heteroaryl or C1 -C10 alkoxycarbonyl, CO2 R5 or --C(═O)N(R5)R5a ;
R15 is selected from:
H;
R6 ;
C1 -C10 alkyl, substituted with 0-8 R6 ;
C2 -C10 alkenyl, substituted with 0-6 R6 ;
C1 -C10 alkoxy, substituted with 0-6 R6 ;
aryl, substituted with 0-5 R6 ;
- 6membered heterocyclic ring containing 1-2 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-5 R6 ;
C1 -C10 alkoxycarbonyl substituted with 0-8 R6 ;
CO2 R5 ; or
--C(═O)N(R5)R5a ;
provided that when b is a double bond, only one of R14 or R15 is present;
n is 0-4;
q is 2-7;
r is 0-3;
provided that n, q, and r are chosen such that the number of atoms connecting R1 and Y is in the range of 8-18.
2. A compound of claim 1 of Formula II: ##STR383## wherein: R1 is selected from R2 HN(CH2)q O--, R2 HN(R2 N)CNH(CH2)q O--, piperazinyl-(CH2)q O--, or ##STR384## R2 is selected from H, aryl(C1 -C10 alkoxy)carbonyl, C1 -C10 alkoxycarbonyl;
R8 is selected from H, C1 -C10 alkyl, C2 -C10 alkenyl, C3 -C8 cycloalkyl, C5 -C6 cycloalkenyl, aryl, 5-6 membered heterocyclic ring containing 1-2 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated;
R6 and R7 are selected from H, C1 -C10 alkyl, hydroxy, C1 -C10 alkoxy, nitro, C1 -C10 alkylcarbonyl, --N(R12)R13, cyano, or halo.
3. A compound of claim 2 wherein:
X is selected from:
a single bond;
--(C1 -C7 alkyl)-, substituted with 0-2 groups independently selected from R4, R8 or R14 ;
--(C2 -C7 alkenyl)-, substituted with 0-2 groups independently selected from R4, R8 or R14 ;
--(C2 -C7 alkynyl)-, substituted with 0-2 groups independently selected from R4, R8 or R14 ;
R8 is selected from H, C1 -C6 alkyl, C2 -C6 alkenyl, C3 -C8 cycloalkyl, C5 -C6 cycloalkenyl, aryl, 5-6 membered heterocyclic ring containing 1-2 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated.
4. A compound of claim 2 wherein:
R1 is ##STR385## V is phenylene or pyridylene; n is 1 or 2;
X is --(C1 -C2)alkyl-substituted with 0-2 R4
Y is selected from:
hydroxy;
C1 to C10 alkoxy;
methylcarbonyloxymethoxy-;
ethylcarbonyloxymethoxy-;
t-butylcarbonyloxymethoxy-;
cyclohexylcarbonyloxymethoxy-;
1-(methylcarbonyloxy)ethoxy-;
1-(ethylcarbonyloxy)ethoxy-;
1-(t-butylcarbonyloxy)ethoxy-;
1-(cyclohexylcarbonyloxy)ethoxy-;
i-propyloxycarbonyloxymethoxy-;
t-butyloxycarbonyloxymethoxy-;
1-(i-propyloxycarbonyloxy)ethoxy-;
1-(cyclohexyloxycarbonyloxy)ethoxy-;
1-(t-butyloxycarbonyloxy)ethoxy-;
dimethylaminoethoxy-;
diethylaminoethoxy-;
(5-methyl-1,3-dioxacyclopenten-2-on-4-yl)methoxy-;
(5-(t-butyl)-1,3-dioxacyclopenten-2-on-4-yl)methoxy-;
(1,3-dioxa-5-phenyl-cyclopenten-2-on-4-yl)methoxy-;
1-(2-(2-methoxypropyl)carbonyloxy)ethoxy-;
R4 is --NR12 R13 ;
R12 is H, C1 -C4 alkoxycarbonyl, C1 -C4 alkylcarbonyl, C1 -C4 alkylsulfonyl, arylalkylsulfonyl, heteroarylsulfonyl, arylsulfonyl, benzyl, benzoyl, phenoxycarbonyl, benzyloxycarbonyl, arylalkylsulfonyl, pyridylcarbonyl, or pyridylmethylcarbonyl;
R13 is H.
5. A compound of claim 1, or a pharmaceutically acceptable salt form thereof, selected from:
5(R,S) -3-[[4-(2-piperidin-4-yl)ethoxyphenyl]isoxazolin-5-yl]acetic acid;
5(R,S)-N-(butanesulfonyl)-L-{3-[4-(2-piperidin-4-yl)ethoxyphenyl]isoxazolin-5-yl}glycine;
5(R,S)-N-(α-toluenesulfonyl)-L-{3-[4-(2-piperidin-4-yl)ethoxyphenyl]isoxazolin-5-yl}glycine;
5(R,S) -N-[(benzyloxy)carbonyl]-L-{3-[4-(2-piperidin-4-yl)ethoxyphenyl]isoxazolin-5-yl}glycine;
5(R,S)-N-(pentanoyl)-L-{3-[4-(2-piperidin-4-yl)ethoxyphenyl]isoxazolin-5-yl}glycine;
5(R,S)-3-{[4-(piperidin-4-yl)methoxyphenyl]isoxazolin-5-yl}propanoic acid;
2(R,S)-5(R,S)-N-(butanesulfonyl)amino-{3-[4-(piperidin-4-yl)methoxyphenyl]isoxazolin-5-yl}propanoic acid;
2(R,S)-5(R,S)-N-(α-toluenesulfonyl)amino-{3-[4-(piperidin-4-yl)methoxyphenyl]isoxazolin-5-yl}propanoic acid;
2(R,S)-5(R,S)-N-[(benzyloxy)carbonyl]amino-{3-[4-(piperidin-4-yl)methoxyphenyl]isoxazolin-5-yl}propanoic acid;
2(R,S)-5(R,S)-N-(pentanoyl)amino-{3-[4-(piperidin-4-yl)methoxyphenyl]isoxazolin-5-yl}propanoic acid.
6. A compound of Formula Id: ##STR386## or a pharmaceutically acceptable salt form thereof wherein: R1 is selected from is selected from R2 (R3)N--, R2 (R3)N(R2 N═)C--, R2 (R3)N(R2 N═)CN(R2)--, R2 (R3)N(CH2)q Z--, R2 (R3)N(R2 N═)C(CH2)q Z--, R2 (R3)N(R2 N═)CN(R2)(CH2)q Z--, piperazinyl-(CH2)q Z--, R2 (R3)NC(O)--, R2 (R5 O)N(R2 N═)C--, R2 (R3)N(R5 ON═)C--, ##STR387## Z is selected from a bond, O, S, S(═O), or S(═O)2 ; R2 and R3 are independently selected from: H; C1 -C10 alkyl; C3 -C6 alkenyl; C3 -C11 cycloalkyl; C4 -C11 cycloalkylalkyl; C6 -C10 aryl optionally substituted with 0-3 groups selected from hydroxy, halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m CH3, --N(CH3)2, C1 -C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C7 -C11 arylalkyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m CH3, --N(CH3)2, C1 -C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C2 -C7 alkylcarbonyl; C7 -C11 arylcarbonyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m CH3, --N(CH3)2, C1 -C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C1 -C10 alkoxycarbonyl; C4 -C11 cycloalkoxycarbonyl; C7 -C11 bicycloalkoxycarbonyl; C7 -C11 aryloxycarbonyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m CH3, --N(CH3)2, C1 -C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; aryl(C1 -C10 alkoxy)carbonyl where the aryl group is optionally substituted with 0-3 groups selected from hydroxy, halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m CH3, --N(CH3)2, C1 -C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C1 -C6 alkylcarbonyloxy(C1 -C4 alkoxy)carbonyl; C6 -C10 arylcarbonyloxy(C1 -C4 alkoxy)carbonyl where the aryl group is optionally substituted with 0-3 groups selected from hydroxy, halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m CH3, --N(CH3)2, C1 -C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C4 -C11 cycloalkylcarbonyloxy(C1 -C4 alkoxy)carbonyl; heteroaryl optionally substituted with 0-2 groups selected from hydroxy, halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m CH3, --N(CH3)2, C1 -C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; or heteroaryl(C1 -C5)alkyl where the heteroaryl group is optionally substituted with 0-2 groups selected from hydroxy, halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m CH3, --N(CH3)2, C1 -C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl;
provided that only one of R2 and R3 may be hydroxy;
U is selected from:
a single bond,
C1 -C7 alkylene,
C2 -C7 alkenylene,
C2 -C7 alkynylene,
arylene substituted with 0-3 R6a, or
pyridylene substituted with 0-3 R6a ;
V is selected from:
a single bond;
C1 -C7 alkylene substituted with 0-6 R6 or R7 ;
C2 -C7 alkenylene substituted with 0-4 R6 or R7 ;
C2 -C7 alkynylene substituted with 0-4 R6 or R7 ;
phenylene substituted with 0-4 R6 or R7 ;
pyridylene substituted with 0-3 R6 or R7 ;
pyridazinylene substituted with 0-3 R6 or R7 ;
X is selected from:
a single bond;
--(CH2)n C(═O)N(R12)--;
C1 -C7 alkylene substituted with 0-6 R4, R8 or R15 ;
C2 -C7 alkenylene substituted with 0-4 R4, R8 or R15 ;
C2 -C7 alkynylene substituted with 0-4 R4, R8 or R15 ;
Y is selected from:
hydroxy,
C1 to C10 alkyloxy,
C3 to C11 cycloalkyloxy,
C6 to C10 aryloxy,
C7 to C11 aralkyloxy,
C3 to C10 alkylcarbonyloxyalkyloxy,
C3 to C10 alkoxycarbonyloxyalkyloxy,
C2 to C10 alkoxycarbonylalkyloxy,
C5 to C10 cycloalkylcarbonyloxyalkyloxy,
C5 to C10 cycloalkoxycarbonyloxyalkyloxy,
C5 to C10 cycloalkoxycarbonylalkyloxy,
C7 to C11 aryloxycarbonylalkyloxy,
C8 to C12 aryloxycarbonyloxyalkyloxy,
C8 to C12 arylcarbonyloxyalkyloxy,
C5 to C10 alkoxyalkylcarbonyloxyalkyloxy,
C5 to C10 (5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy,
C10 to C14 (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy;
(R2) (R3)N--(C1 -C10 alkoxy)-;
R14 and W are attached to the same carbon and taken together to form a spiro-fused, 5-7 membered ring structure of the formula: ##STR388## D, E, F and G are each independently selected from: C(R6a)2 ;
carbonyl;
a heteroatom moiety selected from N, N(R12), O, provided that no more than 2 of D, E, F and G are N, N(R12), O, S, or C(═O);
alternatively, the bond between D and E, E and F, or F and G in such spiro-fused ring may be a carbon-nitrogen double bond or a carbon-carbon double bond;
R4 is selected from H, C1 -C10 alkyl, hydroxy, C1 -C10 alkoxy, nitro, C1 -C10 alkylcarbonyl, or --N(R12)R13 ;
R6 and R7 are each independently selected from H, C1 -C10 alkyl, hydroxy, C1 -C10 alkoxy, nitro, C1 -C10 alkylcarbonyl, --N(R12)R13, cyano, halo, CF3, CHO, CO2 R5a, C(═O)R5a, CONHR5a, CON(R12)2, OC(═O)R5a, OC(═O)OR5a, OR5a, OC(═O)N(R12)2, OCH2 CO2 R5a, CO2 CH2 CO2 R5a, N(R12)2, NO2, NR12 C(═O) R5a, NR12 C(═O)OR5a, NR12 C(═O)N(R12)2, NR12 SO2 N(R12)2, NR12 SO2 R5a, S(O)p R5a, SO2 N(R12)2, C2 to C6 alkenyl, C3 to C11 cycloalkyl, C4 to C11 cycloalkylmethyl;
C6 to C10 aryl optionally substituted with 1-3 groups selected from halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m Me, or --NMe2 ;
C7 to C11 arylalkyl, said aryl being optionally substituted with 1-3 groups selected from halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m Me, or --NMe2 ;
methylenedioxy when R6 is a substituent on aryl;
R6a is selected from C1 -C4 alkyl, C1 -C4 alkoxy, halo, CF3, NO2, or NR12 R13 ;
R8 is selected from:
H;
R6 ;
C1 -C10 alkyl, substituted with 0-8 R6 ;
C2 -C10 alkenyl, substituted with 0-6 R6 ;
C2 -C10 alkynyl, substituted with 0-6 R6 ;
C3 -C8 cycloalkyl, substituted with 0-6 R6 ;
C5 -C6 cycloalkenyl, substituted with 0-5 R6 ;
aryl, substituted with 0-5 R6 ;
- 6membered heterocyclic ring containing 1-2 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-5 R6 ;
R12 and R13 are independently H, C1 -C10 alkyl, C1 -C10 alkoxycarbonyl, C1 -C10 alkylcarbonyl, C1 -C10 alkylsulfonyl, aryl(C1 -C10 alkyl)sulfonyl, arylsulfonyl, aryl, C2 -C6 alkenyl, C3 -C11 cycloalkyl, C4 -C11 cycloalkylalkyl, C7 -C11 arylalkyl, C2 -C7 alkylcarbonyl, C7 -C11 arylcarbonyl, C2 -C10 alkoxycarbonyl, C4 -C11 cycloalkoxycarbonyl, C7 -C11 bicycloalkoxycarbonyl, C7 -C11 aryloxycarbonyl, heteroarylcarbonyl, heteroarylsulfonyl, heteroarylalkylcarbonyl or aryl(C1 -C10 alkoxy)carbonyl, wherein said aryl groups and heteroaryl groups are optionally substituted with 0-3 substituents selected from: C1 -C4 alkyl, C1 -C4 alkoxy, halo, CF3, and NO2 ;
R5 and R5a are selected independently from H, C1 to C8 alkyl, C2 to C6 alkenyl, C3 to C11 cycloalkyl, C4 to C11 cycloalkylmethyl, C6 to C10 aryl, C7 to C11 arylalkyl, or C1 -C10 alkyl substituted with 0-8 R4 ;
R15 is selected from:
H;
R6 ;
C1 -C10 alkyl, substituted with 0-8 R6 ;
C2 -C10 alkenyl, substituted with 0-6 R6 ;
C1 -C10 alkoxy, substituted with 0-6 R6 ;
aryl, substituted with 0-5 R6 ;
- 6membered heterocyclic ring containing 1-2 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-5 R6 ;
C1 -C10 alkoxycarbonyl substituted with 0-8 R6 ;
CO2 R5 ; or
--C(═O)N(R12)R13 ;
n is 0-4;
p is 1-3;
q is 1-7;
r is 0-3;
provided that n, p, q and r are chosen such that the number of atoms connecting R1 and Y is in the range of 8-17.
7. A compound of claim 6 of Formula III: ##STR389## wherein: R1 is selected from R2 HN--, H2 N(R2 N═)C--, H2 N(R2 N═)CNH--, R2 HN(CH2)q O--, H2 N(R2 N═)CNH(CH2)q O--, piperazinyl-(CH2)q O--, R2 (R3)NC(O)--, R2 (R5 O)N(R2 N═)C--, R2 (R3)N(R5 ON═)C--, ##STR390## R2 and R3 are selected from H; C1 -C6 alkyl; C7 -C11 arylalkyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m CH3, --N(CH3)2, C1 -C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; aryl(C1 -C10 alkoxy)carbonyl where the aryl group is optionally substituted with 0-3 groups selected from hydroxy, halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m CH3, --N(CH3)2, C1 -C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; heteroaryl(C1 -C5)alkyl wherein the heteroaryl group is optionally substituted with 0-2 groups selected from hydroxy, halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m CH3, --N(CH3)2, C1 -C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; or C1 -C10 alkoxycarbonyl;
R4 is selected from H, C1 -C10 alkyl, hydroxy, C1 -C10 alkoxy, nitro, C1 -C10 alkylcarbonyl, or --N(R12)R13 ;
V is selected from:
a single bond;
C1 -C7 alkylene substituted with 0-6 R6 or R7 ;
C2 -C7 alkenylene substituted with 0-4 R6 or R7 ;
C2 -C7 alkynylene substituted with 0-4 R6 or R7 ;
phenylene substituted with 0-3 R6 or R7 ;
pyridylene substituted with 0-3 R6 or R7 ;
pyridazinylene substituted with 0-3 R6 or R7 ;
X is selected from --(CH2)n C(═O)N(R12)--, C1 -C7 alkylene substituted with 0-1 R4, C2 -C7 alkenylene, or C2 -C7 alkynylene;
Y is selected from:
hydroxy,
C1 to C10 alkyloxy,
C3 to C11 cycloalkyloxy,
C6 to C10 aryloxy,
C7 to C11 aralkyloxy,
C3 to C10 alkylcarbonyloxyalkyloxy,
C3 to C10 alkoxycarbonyloxyalkyloxy,
C2 to C10 alkoxycarbonylalkyloxy,
C5 to C10 cycloalkylcarbonyloxyalkyloxy,
C5 to C10 cycloalkoxycarbonyloxyalkyloxy,
C5 to C10 cycloalkoxycarbonylalkyloxy,
C7 to C11 aryloxycarbonylalkyloxy,
C8 to C12 aryloxycarbonyloxyalkyloxy,
C8 to C12 arylcarbonyloxyalkyloxy,
C5 to C10 alkoxyalkylcarbonyloxyalkyloxy,
C5 to C10 (5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, or
C10 to C14 (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy;
Z is selected from 0 or CH2 ;
D, E, F and G are each independently selected from:
CH2 ;
carbonyl;
a heteroatom moiety selected from N, NH, O, provided that no more than 2 of D, E, F and G are N, NH, O or S;
alternatively, the bond between D and E, E and F, or F and G in such spiro-fused ring may be a carbon-nitrogen double bond or a carbon-carbon double bond;
R6 and R7 are each independently selected from H, C1 -C10 alkyl, hydroxy, C1 -C10 alkoxy, nitro, C1 -C10 alkylcarbonyl, --N(R12)R13, cyano, or halo;
R12 and R13 are each independently selected from H, C1 -C10 alkyl, C1 -C10 alkoxycarbonyl, C1 -C10 alkylcarbonyl, C1 -C10 alkylsulfonyl, aryl(C1 -C10 alkyl)sulfonyl, arylsulfonyl, heteroarylsulfonyl, heteroarylcarbonyl, heteroaryalkylcarbonyl or aryl;
n is 0-4;
p is 1-3;
q is 1-7;
r is 0-3;
provided that n, p, q and r are chosen such that the number of atoms between R1 and Y is in the range of 8-17.
8. A compound of claim 7 wherein:
R1 is R2 NHC(═NR2)-- and V is phenyl or pyridyl or
R1 is ##STR391## and V is a single bond; n is 1 or 2;
X is C1 -C4 alkylene substituted with 0-1 R4 ;
Y is selected from:
hydroxy;
C1 to C10 alkoxy;
methylcarbonyloxymethoxy-;
ethylcarbonyloxymethoxy-;
t-butylcarbonyloxymethoxy-;
cyclohexylcarbonyloxymethoxy-;
1-(methylcarbonyloxy)ethoxy-;
1-(ethylcarbonyloxy)ethoxy-;
1-(t-butylcarbonyloxy)ethoxy-;
1-(cyclohexylcarbonyloxy)ethoxy-;
i-propyloxycarbonyloxymethoxy-;
t-butyloxycarbonyloxymethoxy-;
1-(i-propyloxycarbonyloxy)ethoxy-;
1-(cyclohexyloxycarbonyloxy)ethoxy-;
1-(t-butyloxycarbonyloxy)ethoxy-;
dimethylaminoethoxy-;
diethylaminoethoxy-;
(5-methyl-1,3-dioxacyclopenten-2-on-4-yl)methoxy-;
(5-(t-butyl)-1,3-dioxacyclopenten-2-on-4-yl)methoxy-;
(1,3-dioxa-5-phenyl-cyclopenten-2-on-4-yl)methoxy-;
1-(2-(2-methoxypropyl)carbonyloxy)ethoxy-;
R12 and R13 are each independently selected from H, C1 -C6 alkyl, C1 -C4 alkoxycarbonyl, C1 -C4 alkylcarbonyl, C1 -C4 alkylsulfonyl, aryl(C1 -C4 alkyl)sulfonyl, heteroarylsulfonyl, arylsulfonyl, heteroarylcarbonyl, heteroaryalkylcarbonyl or aryl; and
R13 is H.
9. A compound of claim 6, or pharmaceutically acceptable salt forms thereof, selected from:
5(R,S)-3-(4-amidinophenyl)-8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro[4.4]non-2-ene-7,9-dione;
5(R,S)-3-(4-amidinophenyl)-8-(3-carboxypropyl)-1-oxa-2,8-diazaspiro[4.4]non-2-ene-7,9-dione;
5(R,S)-3-(4-amidinophenyl)-8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro[4.4]non-2-ene-5-one;
5(R,S)-3-(4-amidinophenyl)-8-(3-carboxypropyl)-1-oxa-2,8-diazaspiro[4.4]non-2-ene-5-one;
5(R,S) -3-(4-amidinophenyl)-8-(2-carboxyethyl)-1-oxa-2-azaspiro[4.4]nona-2,8-diene-5-one;
5(R,S)-3-(4-amidinophenyl)-8-(3-carboxypropyl)-1-oxa-2-azaspiro[4.4]nona-2,8-diene-5-one;
5(R,S) -3-(4-amidinophenyl)-8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro[4.4]dec-2-ene-7,9-dione;
5(R,S)-3-(4-amidinophenyl)-8-(3-carboxypropyl)-1-oxa-2,8-diazaspiro[4.4]dec-2-ene-7,9-dione;
5(R,S) -3-(4-amidinophenyl)-8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro[4.4]dec-2-ene-5-one;
5(R,S)-3-(4-amidinophenyl)-8-(3-carboxypropyl)-1-oxa-2,8-diazaspiro[4.4]dec-2-ene-5-one;
5(R,S)-3-(4-amidinophenyl)-8-(2-carboxyethyl)-1-oxa-2-azaspiro[4.4]deca-2,8-diene-5-one;
5(R,S)-3-(4-amidinophenyl)-8-(3-carboxypropyl)-1-oxa-2-azaspiro[4.4]deca-2,8-diene-5-one;
5(R,S)-3-(4-amidinophenyl)-8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro[4.4]undec-2-ene-7,9-dione;
5(R,S)-3-(4-amidinophenyl)-8-(3-carboxypropyl)-1-oxa-2,8-diazaspiro[4.4]undec-2-ene-7,9-dione;
5(R,S) -3-(4-amidinophenyl)-8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro[4.4]undec-2-ene-5-one;
5(R,S)-3-(4-amidinophenyl)-8-(3-carboxypropyl)-1-oxa-2,8-diazaspiro[4.4]undec-2-ene-5-one;
5(R,S)-3-(4-amidinophenyl)-8-(2-carboxyethyl)-1-oxa-2-azaspiro[4.4]undeca-2,8-diene-5-one;
5(R,S) -3-(4-amidinophenyl)-8-(3-carboxypropyl)-1-oxa-2-azaspiro[4.4]undeca-2,8-diene-5-one;
5(R,S)-3-[2-(piperidin-4-yl)ethyl]-8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro[4.4]non-2-ene-7,9-dione;
5(R,S) -3-[2-(piperidin-4-yl)ethyl]-8-(3-carboxypropyl)-1-oxa-2,8-diazaspiro[4.4]non-2-ene-7,9-dione;
5(R,S)-3-[2-(piperidin-4-yl)ethyl]-8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro[4.4]non-2-ene-5-one;
5(R,S)-3-[2-(piperidin-4-yl)ethyl]-8-(3-carboxypropyl)-1-oxa-2,8-diazaspiro[4.4]non-2-ene-5-one;
5(R,S)-3-[2-(piperidin-4-yl)ethyl]-8-(2-carboxyethyl)-1-oxa-2-azaspiro[4.4]nona-2,8-diene-5-one;
5(R,S)-3-[2-(piperidin-4-yl)ethyl]-8-(3-carboxypropyl)-1-oxa-2-azaspiro[4.4]nona-2,8-diene-5-one;
5(R,S)-3-[2-(piperidin-4-yl)ethyl]-8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro[4.4]dec-2-ene-7,9-dione;
5(R,S)-3-[2-(piperidin-4-yl)ethyl]-8-(3-carboxypropyl)-1-oxa-2,8-diazaspiro[4.4]dec-2-ene-5,7-dione;
5(R,S)-3-[2-(piperidin-4-yl)ethyl]-8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro[4.4]dec-2-ene-5-one;
5(R,S) -3-[2-(piperidin-4-yl)ethyl]-8-(3-carboxypropyl)-1-oxa-2,8-diazaspiro[4.4]dec-2-ene-5-one;
5(R,S)-3-[2-(piperidin-4-yl)ethyl]-8-(2-carboxyethyl)-1-oxa-2-azaspiro[4.4]deca-2,8-diene-5-one;
5(R,S)-3-[2-(piperidin-4-yl)ethyl]-8-(3-carboxypropyl)-1-oxa-2-azaspiro[4.4]deca-2,8-diene-5-one;
5(R,S) -3-[2-(piperidin-4-yl)ethyl]-8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro[4.4]undec-2-ene-7,9-dione;
5(R,S)-3-[2-(piperidin-4-yl)ethyl]-8-(3-carboxypropyl)-1-oxa-2,8-diazaspiro[4.4]undec-2-ene-7,9-dione;
5(R,S)-3-[2-(piperidin-4-yl)ethyl]-8-(2-carboxyethyl)-1-oxa-2,8-diazaspiro[4.4]undec-2-ene-5-one;
5(R,S)-3-[2-(piperidin-4-yl)ethyl]-8-(3-carboxypropyl)-1-oxa-2,8-diazaspiro[4.4]undec-2-ene-5-one;
5(R,S) -3-[2-(piperidin-4-yl)ethyl]-8-(2-carboxyethyl)-1-oxa-2-azaspiro[4.4]undeca-2,8-diene-5-one;
5(R,S)-3-[2-(piperidin-4-yl)ethyl]-8-(3-carboxypropyl)-1-oxa-2-azaspiro[4.4]undeca-2,8-diene-5-one;
5(R,S)-3-(4-amidinophenyl)-8-[2-(benzyloxycarbonylamino)-2-carboxyethyl]-1-oxa-2,8-diazaspiro[4.5]dec-2-ene.
10. A compound of Formula I: ##STR392## or pharmaceutically acceptable salt form thereof, wherein: b is a carbon-carbon single bond or double bond;
R1 is selected from:
R2 (R3)N(CH2)q Z--, R2 (R3)N(R2 N═)C(CH2)q Z--,
R2 (R3)N(R2 N═)CN(R2)(CH2)q Z--, piperazinyl-(CH2)q Z-- or ##STR393## Z is selected from O, S, S(═O), S(═O)2 ; R2 and R3 are independently selected from: H, C1 -C10 alkyl, C2 -C6 alkenyl, C3 -C11 cycloalkyl, C4 -C11 cycloalkylalkyl, C6 -C10 aryl, C7 -C11 arylalkyl, C2 -C7 alkylcarbonyl, C7 -C11 arylcarbonyl, C2 -C10 alkoxycarbonyl, C4 -C11 cycloalkoxycarbonyl, C7 -C10 bicycloalkoxycarbonyl, C7 -C11 aryloxycarbonyl, or aryl(C1 -C10 alkoxy)carbonyl, C1 -C6 alkylcarbonyloxy(C1 -C4 alkoxy)carbonyl, C6 -C10 arylcarbonyloxy(C1 -C4 alkoxy)carbonyl, C4 -C11 cycloalkylcarbonyloxy(C1 -C4 alkoxy)carbonyl;
U is optionally present and is selected from C1 -C7 alkylene, C2 -C7 alkenylene, C2 -C7 alkynylene, arylene, or pyridylene;
V is selected from:
a single bond;
C1 -C7 alkylene substituted with 0-6 R6 or R7 ;
C2 -C7 alkenylene substituted with 0-4 R6 or R7 ;
C2 -C7 alkynylene substituted with 0-4 R6 or R7 ;
phenylene substituted with 0-4 R6 or R7 ;
pyridylene substituted with 0-3 R6 or R7 ;
pyridazinylene substituted with 0-3 R6 or R7 ;
W is -(aryl)-Z1 --, wherein said aryl is substituted with 0-6 R6 or R7 ;
Z1 is selected from a single bond, --CH2 --, O or S;
X is selected from:
a single bond;
C1 -C7 alkylene substituted with 0-6 R4, R8 or R15 ;
C2 -C7 alkenylene substituted with 0-4 R4, R8 or R15 ;
C2 -C7 alkynylene substituted with 0-4 R4, R8 or R15 ;
Y is selected from hydroxy, C1 to C10 alkyloxy, C3 to C11 cycloalkyloxy, C6 to C10 aryloxy, C7 to C11 aralkyloxy, C3 to C10 alkylcarbonyloxyalkyloxy, C3 to C10 alkoxycarbonyloxyalkyloxy, C2 to C10 alkoxycarbonylalkyloxy, C5 to C10 cycloalkylcarbonyloxyalkyloxy, C5 to C10 cycloalkoxycarbonyloxyalkyloxy, C5 to C10 cycloalkoxycarbonylalkyloxy, C7 to C11 aryloxycarbonylalkyloxy, C8 to C12 aryloxycarbonyloxyalkyloxy, C8 to C12 arylcarbonyloxyalkyloxy, C5 to C10 alkoxyalkylcarbonyloxyalkyloxy, C5 to C10 (5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, C10 to C14 (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy; (R2)(R3)N--(C1 -C10 alkoxy)-;
R4 is selected from H, C1 -C10 alkyl, hydroxy, C1 -C10 alkoxy, nitro, C1 -C10 alkylcarbonyl, or --N(R12)R13 ;
R6 and R7 are each independently selected from H, C1 -C10 alkyl, hydroxy, C1 -C10 alkoxy, nitro, C1 -C10 alkylcarbonyl, --N(R12)R13, cyano, halo, CF3, CHO, CO2 R5a, C(═O)R5a, CONHR5a, CON(R12)2, OC(═O)R5a, OC(═O)OR5a, OR5a, OC(═O)N(R12)2, OCH2 CO2 R5a, CO2 CH2 CO2 R5a, N(R12)2, NO2, NR12 C(═O)R5a, NR12 C(═O)OR5a, NR12 C(═O)N(R12)2, NR12 SO2 N(R12)2, NR12 SO2 R5a, S(O)p R5a, SO2 N(R12)2, C2 to C6 alkenyl, C3 to C11 cycloalkyl, C4 to C11 cycloalkylmethyl;
C6 to C10 aryl optionally substituted with halogen, alkoxy, alkyl, --CF3, S(O)m Me, or --NMe2 ; or
C7 to C11 arylalkyl said aryl being optionally substituted with halogen, alkoxy, alkyl, --CF3, S(O)m Me, or --NMe2 ;
R8 is selected from:
H;
R6 ;
C1 -C10 alkyl, substituted with 0-8 R6 ;
C2 -C10 alkenyl, substituted with 0-6 R6 ;
C2 -C10 alkynyl, substituted with 0-6 R6 ;
C3 -C8 cycloalkyl, substituted with 0-6 R6 ;
C5 -C6 cycloalkenyl, substituted with 0-5 R6 ;
aryl, substituted with 0-5 R6 ;
- 6membered heterocyclic ring containing 1-2 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-5 R6 ;
R12 and R13 are independently H, C1 -C10 alkyl, C1 -C10 alkoxycarbonyl, C1 -C10 alkylcarbonyl, C1 -C10 alkylsulfonyl, aryl(C1 -C10 alkyl)sulfonyl, heteroarylsulfonyl, arylsulfonyl, aryl, C2 -C6 alkenyl, C3 -C11 cycloalkyl, C4 -C11 cycloalkylalkyl, C7 -C11 arylalkyl, C2 -C7 alkylcarbonyl, C7 -C11 arylcarbonyl, C2 -C10 alkoxycarbonyl, C4 -C11 cycloalkoxycarbonyl, C7 -C11 bicycloalkoxycarbonyl, C7 -C11 aryloxycarbonyl, heteroarylcarbonyl, heteroarylalkylcarbonyl or aryl (C1 -C10 alkoxy) carbonyl;
R14 is selected from H, C1 -C10 alkyl, C2 -C10 alkenyl, C2 -C10 alkynyl, C1 -C10 alkoxy, aryl, heteroaryl or C1 -C10 alkoxycarbonyl, CO2 R5 or --C(═O)N(R12)R13 ;
R5 and R5a are selected independently from H, C1 to C8 alkyl, C2 to C6 alkenyl, C3 to C11 cycloalkyl, C4 to C11 cycloalkylmethyl, C6 to C10 aryl, C7 to C11 arylalkyl, or C1 -C10 alkyl substituted with 0-8 R4 ;
R15 is selected from:
H;
R6 ;
C1 -C10 alkyl, substituted with 0-8 R6 ;
C2 -C10 alkenyl, substituted with 0-6 R6 ;
C1 -C10 alkoxy, substituted with 0-6 R6 ;
aryl, substituted with 0-5 R6 ;
- 6membered heterocyclic ring containing 1-2 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-5 R6 ;
C1 -C10 alkoxycarbonyl substituted with 0-8 R6 ;
CO2 R5 ; or
--C(═O)N(R12)R13 ;
n is 0-4;
q is 2-7;
r is 0-3;
provided that n, q, and r are chosen such that the number of atoms between R1 and Y is about 8-17.
11. A compound of claim 10 of Formula IV: ##STR394## wherein: b is a carbon-carbon single bond or double bond;
R1 is selected from R2 HN(CH2)q O--, R2 HN(R2 N═C)NH(CH2)q O--, piperazinyl-(CH2)q O--, or ##STR395## Z is O; R2 is selected from H, aryl(C1 -C10)alkoxycarbonyl, C1 -C10 alkoxycarbonyl;
V is selected from:
a single bond;
C1 -C7 alkylene substituted with 0-6 R6 or R7 ;
C2 -C7 alkenylene substituted with 0-4 R6 or R7 ;
C2 -C7 alkynylene substituted with 0-4 R6 or R7 ;
phenylene substituted with 0-3 R6 or R7 ;
pyridylene substituted with 0-3 R6 or R7 ; pyridazinylene substituted with 0-3 R6 or R7 ;
Z1 is selected from a single bond, O or S;
X is selected from:
a single bond;
C1 -C7 alkylene substituted with 0-4 R4, R8 or R15 ;
C2 -C7 alkenylene substituted with 0-3 R4, R8 or R15 ;
C2 -C7 alkynylene substituted with 0-3 R4, R8 or R15 ;
Y selected from hydroxy, C1 to C10 alkyloxy, C3 to C11 cycloalkyloxy, C6 to C10 aryloxy, C7 to C11 aralkyloxy, C3 to C10 alkylcarbonyloxyalkyloxy, C3 to C10 alkoxycarbonyloxyalkyloxy, C2 to C10 alkoxycarbonylalkyloxy, C5 to C10 cycloalkylcarbonyloxyalkyloxy, C5 to C10 cycloalkoxycarbonyloxyalkyloxy, C5 to C10 cycloalkoxycarbonylalkyloxy, C7 to C11 aryloxycarbonylalkyloxy, C8 to C12 aryloxycarbonyloxyalkyloxy, C8 to C12 arylcarbonyloxyalkyloxy, C5 to C10 alkoxyalkylcarbonyloxyalkyloxy, C5 to C10 (5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, or C10 to C14 (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy;
R4 is selected from H, C1 -C10 alkyl, hydroxy, C1 -C10 alkoxy, nitro, C1 -C10 alkylcarbonyl, or --N(R12)R13 ;
R6 and R7 are selected from H, C1 -C10 alkyl, hydroxy, C1 -C10 alkoxy, nitro, C1 -C10 alkylcarbonyl, --N(R12)R13, cyano, or halo;
R8 is selected from H, C1 -C10 alkyl, C2 -C10 alkenyl, C3 -C8 cycloalkyl, C5 -C6 cycloalkenyl, aryl, 5-6 membered heterocyclic ring containing 1-2 N, O, or S, where said heterocyclic ring may be saturated, partially saturated, or fully unsaturated;
R12 and R13 are independently selected from H, C1 -C10 alkyl, C1 -C10 alkoxycarbonyl, C1 -C10 alkylcarbonyl, C1 -C10 alkylsulfonyl, aryl(C1 -C10 alkyl)sulfonyl, arylsulfonyl, heteroarylcarbonyl, heteroarylsulfonyl, heteroarylalkylcarbonyl or aryl;
R14 is selected from H, C1 -C10 alkyl, C2 -C10 alkenyl, C2 -C10 alkynyl, C1 -C10 alkoxy, aryl, heteroaryl or C1 -C10 alkoxycarbonyl, CO2 R5 or --C(═O)N(R12)R13 ;
R5 is selected from H or C1 -C10 alkyl substituted with 0-6 R4 ;
n is 0-4;
q is 2-7;
provided that n and q are chosen such that the number of atoms between R1 and Y is in the range of 8-17.
12. A compound of claim 1, wherein:
R1 is R2 HN(CH2)q O-- or ##STR396## V is C1 -C3 alkylene; Z1 is a single bond or O;
X is C1 -C3 alkylene substituted with 0-1 R4 ;
Y is selected from:
hydroxy;
C1 to C10 alkoxy;
methylcarbonyloxymethoxy-;
ethylcarbonyloxymethoxy-;
t-butylcarbonyloxymethoxy-;
cyclohexylcarbonyloxymethoxy-;
1-(methylcarbonyloxy)ethoxy-;
1-(ethylcarbonyloxy)ethoxy-;
1-(t-butylcarbonyloxy)ethoxy-;
1-(cyclohexylcarbonyloxy)ethoxy-;
i-propyloxycarbonyloxymethoxy-;
t-butyloxycarbonyloxymethoxy-;
1-(i-propyloxycarbonyloxy)ethoxy-;
1-(cyclohexyloxycarbonyloxy)ethoxy-;
1-(t-butyloxycarbonyloxy)ethoxy-;
dimethylaminoethoxy-;
diethylaminoethoxy-;
(5-methyl-1,3-dioxacyclopenten-2-on-4-yl)methoxy-;
(5-(t-butyl)-1,3-dioxacyclopenten-2-on-4-yl)methoxy-;
(1,3-dioxa-5-phenyl-cyclopenten-2-on-4-yl)methoxy-;
1-(2-(2-methoxypropyl)carbonyloxy)ethoxy-;
R12 and R13 are independently selected from H, C1 -C6 alkyl, C1 -C4 alkoxycarbonyl, C1 -C4 alkylcarbonyl, C1 -C6 alkylsulfonyl, aryl(C1 -C4 alkyl)sulfonyl, arylsulfonyl, heteroarylcarbonyl, heteroarylsulfonyl, heteroarylalkylcarbonyl or aryl;
R13 is H.
13. A compound of claim 10, or a pharmaceutically acceptable salt form thereof, selected from:
5(R,S)-4-[3-(piperidin-4-yl)oxymethylisoxazolin-5-yl]hydrocinnamic acid;
5(R,S)-4-[3-(2-aminoethoxymethyl),isoxazolin-5-yl]hydrocinnamic acid;
5(R,S)-4-[3-(3-aminopropyloxymethyl)isoxazolin-5-yl]hydrocinnamic acid;
5(R,S)-4-[3-(piperidin-4-yl)oxymethylisoxazolin-5-yl]phenoxyacetic acid;
5(R,S)-4-[3-(2-aminoethoxymethyl)isoxazolin-5-yl]phenoxyacetic acid;
5(R,S)-4-[3-(3-aminopropyloxymethyl)isoxazolin-5-yl]phenoxyacetic acid.
14. A compound of Formula I: ##STR397## or a pharmaceutically acceptable salt form thereof wherein: b is a carbon-carbon single or double bond;
R1 is selected from R2a (R3)N--, R2 (R3)N(R2 N═)C--, R2a (R3)N(CH2)q Z--, R2 (R3)N(R2 N═)C(CH2)q Z--, R2 (R3)NC(O)--, R2 (R5 O)N(R2 N═)C--, R2 (R3)N(R5 ON═)C--; ##STR398## Z is selected from a bond, O, S, S(═O), S(═O)2 ;
R2 and R3 are independently selected from: H; C1 -C10 alkyl; C3 -C6 alkenyl; C3 -C11 cycloalkyl; C4 -C11 cycloalkylalkyl; C6 -C10 aryl optionally substituted with 0-3 groups selected from hydroxy, halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m CH3, --N(CH3)2, C1 -C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C7 -C11 arylalkyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m CH3, --N(CH3)2, C1 -C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C2 -C7 alkylcarbonyl; C7 -C11 arylcarbonyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m CH3, --N(CH3)2, C1 -C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C1 -C10 alkoxycarbonyl; C4 -C11 cycloalkoxycarbonyl; C7 -C11 bicycloalkoxycarbonyl; C7 -C11 aryloxycarbonyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m CH3, --N(CH3)2, C1 -C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; aryl(C1 -C10 alkoxy)carbonyl where the aryl group is optionally substituted with 0-3 groups selected from hydroxy, halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m CH3, --N(CH3)2, C1 -C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C1 -C6 alkylcarbonyloxy(C1 -C4 alkoxy)carbonyl; C6 -C10 arylcarbonyloxy(C1 -C4 alkoxy)carbonyl where the aryl group is optionally substituted with 0-3 groups selected from hydroxy, halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m CH3, --N(CH3)2, C1 -C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C4 -C11 cycloalkylcarbonyloxy(C1 -C4 alkoxy)carbonyl; heteroaryl optionally substituted with 0-2 groups selected from hydroxy, halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m CH3, --N(CH3)2, C1 -C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; or heteroaryl(C1 -C5)alkyl where the heteroaryl group is optionally substituted with 0-2 groups selected from hydroxy, halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m CH3, --N(CH3)2, C1 -C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl;
provided that only one of R2 and R3 may be hydroxy;
R2a is R2 or R2 (R3)N(R2 N═)C;
U is selected from:
a single bond,
--(C1 -C7 alkyl)-,
--(C2 -C7 alkenyl)-,
--(C2 -C7 alkynyl)-,
-(aryl)- substituted with 0-3 R6 -, or
-(pyridyl)- substituted with 0-3 R6a ;
V is selected from:
a single bond;
--(C1 -C7 alkyl)-, substituted with 0-3 groups independently selected from R6 or R7 ;
--(C2 -C7 alkenyl)-, substituted with 0-3 groups independently selected from R6 or R7 ;
--(C2 -C7 alkynyl)-, substituted with 0-3 groups independently selected from R6 or R7 ;
-(phenyl)-, substituted with 0-2 groups independently selected from R6 or R7 ;
-(pyridyl)-, substituted with 0-2 groups independently selected from R6 or R7 ; or
-(pyridazinyl)-, substituted with 0-2 groups independently selected from R6 or R7 ;
W is selected from: ##STR399## X is selected from: a single bond,
--(C(R4)2)n --C(R4)(R8)--C(R4)(R4a)--, with the proviso that when n is 0 or 1, then at least one of R4a or R8 is other than H or methyl;
Y selected from:
hydroxy,
C1 to C10 alkyloxy,
C3 to C11 cycloalkyloxy,
C6 to C10 aryloxy,
C7 to C11 aralkyloxy,
C3 to C10 alkylcarbonyloxyalkyloxy,
C3 to C10 alkoxycarbonyloxyalkyloxy,
C2 to C10 alkoxycarbonylalkyloxy,
C5 to C10 cycloalkylcarbonyloxyalkyloxy,
C5 to C10 cycloalkoxycarbonyloxyalkyloxy,
C5 to C10 cycloalkoxycarbonylalkyloxy,
C7 to C11 aryloxycarbonylalkyloxy,
C8 to C12 aryloxycarbonyloxyalkyloxy,
C8 to C12 arylcarbonyloxyalkyloxy,
C5 to C10 alkoxyalkylcarbonyloxyalkyloxy,
C5 to C10 (5-alkyl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy,
C10 to C14 (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy,
(R2)(R3)N--(C1 -C10 alkoxy)-;
Z1 is --C--, --O--, or --NR22 --;
Z2 is --O--, or --NR22 --;
R4 is selected from H, C1 -C10 alkyl, C1 -C10 alkylcarbonyl, aryl, arylalkylene cycloalkyl, or cycloalkylalkylene;
alternately, two R4 groups on adjacent carbon atoms may join to form a bond, thereby to form a carbon-carbon double or triple bond between such adjacent carbon atoms;
R4a is selected from H, hydroxy, C1 -C10 alkoxy, nitro, N(R5)R5a, --N(R12)R13, --N(R16)R17, C1 -C10 alkyl substituted with 0-3 R6, aryl substituted with 0-3 R6, or C1 -C10 alkylcarbonyl;
R4b is selected from H, C1 -C6 alkyl, C2 -C6 alkenyl, C2 -C6 alkynyl, hydroxy, C1 -C6 alkoxy; C1 -C6 alkylthio, C1 -C6 alkylsulfinyl, C1 -C6 alkylsulfonyl, nitro, C1 -C6 alkylcarbonyl, C6 -C10 aryl, --N(R12)R13 ; halo, CF3, CN, C1 -C6 alkoxycarbonyl, carboxy, piperidinyl, or pyridyl;
R5 is selected from H, C1 -C8 alkyl, C2 -C6 alkenyl, C3 -C11 cycloalkyl, C4 -C11 cycloalkylmethyl, C6 -C10 aryl, C7 -C11 arylalkyl, or C1 -C10 alkyl substituted with 0-2 R4b ;
R5a is selected from hydrogen, hydroxy, C1 to C8 alkyl, C2 to C6 alkenyl, C3 to C11 cycloalkyl, C4 to C11 cycloalkylmethyl, C1 -C6 alkoxy, benzyloxy, C6 to C10 aryl, heteroaryl, C7 to C11 arylalkyl, or C1 -C10 alkyl substituted with 0-2 R4b ;
alternately, R5 and R5a when both are substituents on the same nitrogen atom (as in --NR5 R5a) can be taken together with the nitrogen atom to which they are attached to form 3-azabicyclononyl, 1,2,3,4-tetrahydro-1-quinolinyl, 1,2,3,4-tetrahydro-2-isoquinolinyl, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl or 1-piperazinyl, each being optionally substituted with C1 -C6 alkyl, C6 -C10 aryl, heteroaryl, C7 -C11 arylalkyl, C1 -C6 alkylcarbonyl, C3 -C7 cycloalkylcarbonyl, C1 -C6 alkoxycarbonyl, C7 -C11 arylalkoxycarbonyl, C1 -C6 alkylsulfonyl or C6 -C10 arylsulfonyl;
R5b is selected from C1 -C8 alkyl, C2 -C6 alkenyl, C3 -C11 cycloalkyl, C4 -C11 cycloalkylmethyl, C6 -C10 aryl, C7 -C11 arylalkyl, or C1 -C10 alkyl substituted with 0-2 R4b ;
R6 is selected from H, C1 -C10 alkyl, hydroxy, C1 -C10 alkoxy, nitro, C1 -C10 alkylcarbonyl, --N(R12)R13, cyano, halo, CF3, CHO, CO2 R5, C(═O)R5a, CONR5 R5a, OC(═O)R5a, OC(═O)OR5b, OR5, OC(═O)NR5 R5a, OCH2 CO2 R5, CO2 CH2 CO2 R5, NO2, NR5a C(═O)R5a, NR5a C(═O)OR5b, NR5a C(═O) NR5 R5a, NR5a SO2 NR5 R5a, NR5a SO2 R5, S(O)p R5, SO2 NR5 R5a, C2 to C6 alkenyl, C3 to C11 cycloalkyl, C4 to C11 cycloalkylmethyl;
C6 to C10 aryl optionally substituted with 1-3 groups selected from halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m Me, or --NMe2 ;
C7 to C11 arylalkyl, said aryl being optionally substituted with 1-3 groups selected from halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m Me, or --NMe2 ;
methylenedioxy when R6 is a substiuent on aryl; or
a 5-6 membered heterocyclic ring containing 1-2 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R7 ;
R6a is selected from C1 -C4 alkyl, C1 -C4 alkoxy, halo, CF3, NO2, or NR12 R13 ;
R7 is selected from H, C1 -C10 alkyl, hydroxy, C1 -C10 alkoxy, nitro, C1 -C10 alkylcarbonyl, --N(R12)R13, cyano, halo, CF3, CHO, CO2 R5, C(═O)R5a, CONR5 R5a, OC(═O)R5a, OC(═O)OR5b, OR5a, OC(═O)NR5 R5a, OCH2 CO2 R5, CO2 CH2 CO2 R5, NO2, NR5a C(═O)R5a, NR5a C(═O)OR5b, NR5a C (═O) NR5 R5a, NR5a SO2 NR5 R5a, NR5a SO2 R5, S(O)m R5a, SO2 NR5 R5a, C2 to C6 alkenyl, C3 to C11 cycloalkyl, C4 to C11 cycloalkylmethyl, C6 to C10 aryl, or C7 to C11 arylalkyl;
R8 is selected from:
R6 ;
C2 -C10 alkyl, substituted with 0-3 R6 ;
C2 -C10 alkenyl, substituted with 0-3 R6 ;
C2 -C10 alkynyl, substituted with 0-3 R6 ;
C3 -C8 cycloalkyl, substituted with 0-3 R6 ;
C5 -C6 cycloalkenyl, substituted with 0-3 R6 ;
aryl, substituted with 0-3 R6 ;
- 6membered heterocyclic ring containing 1-2 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R6 ;
R12 and R13 are independently H, C1 -C10 alkyl, C1 -C10 alkoxycarbonyl, C1 -C10 alkylcarbonyl, C1 -C10 alkylsulfonyl, aryl(C1 -C10 alkyl)sulfonyl, heteroarylsulfonyl, arylsulfonyl, aryl, C2 -C6 alkenyl, C3 -C11 cycloalkyl, C4 -C11 cycloalkylalkyl, C7 -C11 arylalkyl, C7 -C11 arylcarbonyl, C4 -C11 cycloalkoxycarbonyl, C7 -C11 bicycloalkoxycarbonyl, C7 -C11 aryloxycarbonyl, or aryl(C1 -C10 alkoxy)carbonyl, wherein said aryls are optionally substituted with 0-3 substituents selected from the group consisting of: C1 -C4 alkyl, C1 -C4 alkoxy, halo, CF3, and NO2 ;
R14 is selected from H, C1 -C10 alkyl, C2 -C10 alkenyl, C2 -C10 alkynyl, C1 -C10 alkoxy, aryl, heteroaryl or C1 -C10 alkoxycarbonyl, CO2 R5 or --C(═O)N(R5)R5a ;
R15 is selected from:
H;
R6 ;
C1 -C10 alkyl, substituted with 0-3 R6 ;
C2 -C10 alkenyl, substituted with 0-3 R6 ;
C1 -C10 alkoxy, substituted with 0-3 R6 ;
aryl, substituted with 0-3 R6 ;
- 6membered heterocyclic ring containing 1-2 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R6 ;
C1 -C10 alkoxycarbonyl substituted with 0-2 R6 ;
--CO2 R5 ; or
--C(═O)N(R12)R13 ;
provided that when b is a double bond, only one of R14 or R15 is present;
R16 is selected from:
--C(═O)--O--R18a,
--C(═O)--R18b,
--C(═O)N(R18b)2,
--C(═O)NHSO2 R18a,
--C(═O)NHC(═O)R18b,
--C(═O)NHC(═O)OR18a,
--C(═O)NHSO2 NHR18b,
--C(═S)--NH--R18b,
--NH--C(═O)--O--R18a,
--NH--C(═O)--R18b,
--NH--C(═O)--NH--R18b,
--SO2 --O--R18a,
--SO2 --R18a,
--SO2 --N(18b)2,
--SO2 --NHC(═O)O18b,
--P(═S)(OR18a)2,
--P(═O)(OR18a)2,
--P(═S)(R18a)2, ##STR400## or R17 is selected from: H, C1 -C10 alkyl, C2 -C6 alkenyl, C3 -C11 cycloalkyl, C4 -C15 cycloalkylalkyl, aryl, aryl(C1 -C10 alkyl)-;
R18a is selected from:
C1 -C8 alkyl substituted with 0-2 R19,
C2 -C8 alkenyl substituted with 0-2 R19,
C2 -C8 alkynyl substituted with 0-2 R19,
C3 -C8 cycloalkyl substituted with 0-2 R19,
aryl substituted with 0-4 R19,
aryl(C1 -C6 alkyl)- substituted with 0-4 R19,
a 5-10 membered heterocyclic ring system having 1-3 heteroatoms selected independently from O, S, and N, said heterocyclic ring being substituted with 0-4 R19,
C1 -C6 alkyl substituted with a 5-10 membered heterocyclic ring system having 1-3 heteroatoms selected independently from O, S, and N, said heterocyclic ring being substituted with 0-4 R19 ;
R18b is selected from R18a or H;
R19 is selected from H, halogen, CF3, CN, NO2, NR12 R13, C1 -C8 alkyl, C2 -C6 alkenyl, C2 -C6 alkynyl, C3 -C11 cycloalkyl, C4 -C11 cycloalkylalkyl, aryl, aryl(C1 -C6 alkyl)-, C1 -C6 alkoxy, or C1 -C4 alkoxycarbonyl;
R20 and R21 are each independently selected from H, C1 -C10 alkyl, CO2 R5, C(═O)R5a, CONR5 R5a, NR5 C(═O)R5a, NR12 R13, C2 -C6 alkenyl, C3 -C11 cycloalkyl, C4 -C11 cycloalkylmethyl, C6 -C10 aryl, or C7 -C11 arylalkyl;
R22 is selected from C1 -C10 alkyl, C2 -C6 alkenyl, C3 -C11 cycloalkyl, C4 -C15 cycloalkylalkyl, aryl, aryl(C1 -C10 alkyl)-; C(═O)R5a, CO2 R5b, --C(═O)N(R5)R5a, or a bond to X;
m is 0-2;
n is 0-2;
p is 1-2;
q is 1-7;
r is 0-3;
provided that n, q and r are chosen such that the number of atoms connecting R1 and Y is in the range of 8-17.
15. A compound of claim 14 of Formula Ic: ##STR401## wherein: Z is selected from a bond, O, or S;
R2 and R3 are independently selected from: H; C1 -C6 alkyl; C7 -C11 arylalkyl optionally substituted with 0-3 groups selected from hydroxy, halogen, C1 -C6 alkoxy; C1 -C6 alkyl, CF3, S(O)m CH3, --N(CH3)2, C1 -C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; C1 -C10 alkoxycarbonyl; aryl(C1 -C10 alkoxy)carbonyl where the aryl group is optionally substituted with 0-3 groups selected from hydroxy, halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m CH3, --N(CH3)2, C1 -C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl; or heteroaryl(C1 -C5)alkyl wherein the heteroaryl group is optionally substituted with 0-2 groups selected from hydroxy, halogen, C1 -C6 alkoxy, C1 -C6 alkyl, CF3, S(O)m CH3, --N(CH3)2, C1 -C4 haloalkyl, methylenedioxydiyl, ethylenedioxydiyl;
U is a single bond;
X is --CHR4a --;
R5 is selected from H or C1 -C10 alkyl substituted with 0-6 R4b ;
R6 and R7 are each independently selected from H, C1 -C10 alkyl, hydroxy, C1 -C10 alkoxy, nitro, C1 -C10 alkylcarbonyl, --N(R12)R13, cyano, or halo;
R12 and R13 are each independently selected from H, C1 -C10 alkyl, C1 -C10 alkoxycarbonyl, C1 -C10 alkylcarbonyl, C1 -C10 alkylsulfonyl, aryl(C1 -C10 alkyl)sulfonyl, arylsulfonyl, heteroarylsulfonyl, or aryl, wherein said aryls are optionally substituted with 0-3 substituents selected from the group consisting of: C1 -C4 alkyl, C1 -C4 alkoxy, halo, CF3, and NO2 ;
R15 is selected from H, C1 -C10 alkyl, C2 -C10 alkenyl, C2 -C10 alkynyl, C1 -C10 alkoxy, aryl, heteroaryl or C1 -C10 alkoxycarbonyl, CO2 R5 or --C(═O)N(R5)R5a ;
R16 is selected from:
--C(═O)--O--R18a,
--C(═O)--R18b,
--S(═O)2 --R18a ;
R17 is selected from: H or C1 -C4 alkyl;
R18a is selected from:
C1 -C8 alkyl substituted with 0-2 R19,
C2 -C8 alkenyl substituted with 0-2 R19,
C2 -C8 alkynyl substituted with 0-2 R19,
C3 -C8 cycloalkyl substituted with 0-2 R19,
aryl substituted with 0-2 R19,
aryl(C1 -C6 alkyl)- substituted with 0-2 R19,
a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, isoxazolyl, isoxazolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyridinyl, 3H-indolyl, carbazolyl, pyrrolidinyl, piperidinyl, indolinyl, or morpholinyl, said heterocyclic ring being substituted with 0-2 R19 ;
C1 -C6 alkyl substituted with a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, isoxazolinyl, benzofuranyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyridinyl, 3H-indolyl, indolyl, carbazole, pyrrolidinyl, piperidinyl, indolinyl, or morpholinyl, said heterocyclic ring being substituted with 0-2 R19.
16. A compound of claim 14 of Formula Ib: ##STR402## wherein: R1 is selected from: R2 (R3)N--, R2 NH(R2 N═)C--, R2 R3 N(CH2)p" Z--, R2 NH(R2 N═)CNH(CH2)p' Z--, R2 (R3)NC(O)--, R2 (R5 O)N(R2 N═)C--, R2 (R3)N(R5 ON═)C--; ##STR403## n is 0-1; p' is 2-4;
p" is 4-6;
Z is selected from a bond or O;
R3 is H or C1 -C5 alkyl;
V is a single bond, or -(phenyl)-;
X is selected from:
--CH2 --,
--CHN(R16)R17 --, or
--CHNR5 R5a --;
Y is selected from:
hydroxy;
C1 to C10 alkoxy;
methylcarbonyloxymethoxy-;
ethylcarbonyloxymethoxy-;
t-butylcarbonyloxymethoxy-;
cyclohexylcarbonyloxymethoxy-;
1-(methylcarbonyloxy)ethoxy-;
1-(ethylcarbonyloxy)ethoxy-;
1-(t-butylcarbonyloxy)ethoxy-;
1-(cyclohexylcarbonyloxy)ethoxy-;
i-propyloxycarbonyloxymethoxy-;
t-butyloxycarbonyloxymethoxy-;
1-(i-propyloxycarbonyloxy)ethoxy-;
1-(cyclohexyloxycarbonyloxy)ethoxy-;
1-(t-butyloxycarbonyloxy)ethoxy-;
dimethylaminoethoxy-;
diethylaminoethoxy-;
(5-methyl-1,3-dioxacyclopenten-2-on-4-yl)methoxy-;
(5-(t-butyl)-1,3-dioxacyclopenten-2-on-4-yl)methoxy-;
(1,3-dioxa-5-phenyl-cyclopenten-2-on-4-yl)methoxy-;
1-(2-(2-methoxypropyl)carbonyloxy)ethoxy-;
R18a is selected from:
C1 -C4 alkyl substituted with 0-2 R19,
C2 -C4 alkenyl substituted with 0-2 R19,
C2 -C4 alkynyl substituted with 0-2 R19,
C3 -C4 cycloalkyl substituted with 0-2 R19,
aryl substituted with 0-2 R19,
aryl(C1 -C4 alkyl)- substituted with 0-2 R19,
a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, isoxazolyl, isoxazolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyridinyl, 3H-indolyl, carbazolyl, pyrrolidinyl, piperidinyl, indolinyl, or morpholinyl, said heterocyclic ring being substituted with 0-2 R19 ;
C1 -C6 alkyl substituted with a heterocyclic ring system selected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, isoxazolyl, isoxazolinyl, benzofuranyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyridinyl, 3H-indolyl, indolyl, carbazole, pyrrolidinyl, piperidinyl, indolinyl, or morpholinyl, said heterocyclic ring being substituted with 0-2 R19.
17. A compound of claim 16 wherein:
R1 is R2 NH(R2 N═)C-- or R2 NH(R2 N═)CNH-- and V is phenyl or pyridyl; or
R1 is ##STR404## and V is a single bond; n is 1-2;
R3 is H or C1 -C5 alkyl;
X is selected from:
--CH2 --,
--CHN(R16)R17 --, or
--CHNR5 R5a --;
W is selected from: ##STR405## m is 1-3; Y is selected from:
hydroxy;
C1 to C10 alkoxy;
methylcarbonyloxymethoxy-;
ethylcarbonyloxymethoxy-;
t-butylcarbonyloxymethoxy-;
cyclohexylcarbonyloxymethoxy-;
1-(methylcarbonyloxy)ethoxy-;
1-(ethylcarbonyloxy)ethoxy-;
1-(t-butylcarbonyloxy)ethoxy-;
1-(cyclohexylcarbonyloxy)ethoxy-;
i-propyloxycarbonyloxymethoxy-;
t-butyloxycarbonyloxymethoxy-;
1-(i-propyloxycarbonyloxy)ethoxy-;
1-(cyclohexyloxycarbonyloxy)ethoxy-;
1-(t-butyloxycarbonyloxy)ethoxy-;
dimethylaminoethoxy-;
diethylaminoethoxy-;
(5-methyl-1,3-dioxacyclopenten-2-on-4-yl)methoxy-;
(5-(t-butyl)-1,3-dioxacyclopenten-2-on-4-yl)methoxy-;
(1,3-dioxa-5-phenyl-cyclopenten-2-on-4-yl)methoxy-;
1-(2-(2-methoxypropyl)carbonyloxy)ethoxy-;
R19 is H, halogen, C1 -C4 alkyl, C3 -C7 cycloalkyl, cyclopropylmethyl, aryl, or benzyl;
R20 and R21 are both H;
R22 is H, C1 -C4 alkyl or benzyl.
18. A compound of claim 14, or a pharmaceutically acceptable salt form thereof, selected from:
2-(R,S)-2-carboxymethyl-1-{5-(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-yl acetyl]piperidine;
2-(R,S)-2-carboxymethyl-1-{5-(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-yl acetyl]azepine;
2-(R,S)-2-carboxymethyl-1-{5-(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-yl acetyl]pyrrolidine;
3-(R,S)-carboxymethyl-4-{5-(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-yl acetyl]piperazine-2-one;
6-(R,S)-carboxymethyl-1-{5-(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-yl acetyl]piperidine-2-one;
5-(R,S)-carboxymethyl-1-{5-(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-yl acetyl]pyrrolidine-2-one;
7-(R,S)-carboxymethyl-1-{5-(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-yl acetyl]azetidine-2-one;
2-(R,S)-carboxymethyl-1-{5-(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-yl acetyl]pyrazolidine;
3-(R,S)-carboxymethyl-4-(5-(R,S)-N-[3-(4-amidinophenyl)isoxazolin-5-yl acetyl]morpholine.
19. A method for the prevention or treatment of thrombosis which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of claim 1.
20. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1, and a pharmaceutically acceptable carrier.
21. A method of inhibiting the aggregation of blood platelets which comprises administering to a host in need of such inhibition a therapeutically effective amount of a compound of claim 1.
22. A method of treating thromboembolic disorders selected from thrombus or embolus formation, harmful platelet aggregation, reocclusion following thrombolysis, reperfusion injury, restenosis, atherosclerosis, stroke, myocardial infarction, and unstable angina, which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of claim 16.
23. A method for the treatment of thrombosis which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of claim 16 in combination with one or more additional therapeutic agents selected from: a thrombolytic agent, an anti-coagulant agent, or an anti-platelet agent.
24. A method of treating rheumatoid arthritis, asthma, allergies, adult respiratory syndrome, organ transplantation rejection, septic shock, psoriasis, contact dermatitis, osteoporosis, osteoarthritis, tumor metastasis, diabetic retinopathy, inflammatory conditions and inflammatory bowel disease, comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of claim 16.
25. A pharmaceutical composition for intranasal administration, said composition comprising a therapeutically effective amount of a compound of claim 1, a pharmaceutically acceptable excipient, and water.
26. A method of administering a compound of claim 1, said method comprising intranasally administering, to a patient in need of such treatment, a therapeutically effective amount of a pharmaceutical composition containing said compound.
27. A pharmaceutical composition for intranasal administration, said composition comprising a therapeutically effective amount of a compound of claim 1, a pharmaceutically acceptable excipient, and water.
28. A method of administering a compound of claim 1, said method comprising intranasally administering, to a patient in need of such treatment, a therapeutically effective amount of a pharmaceutical composition containing said compound.
29. A pharmaceutical composition for intranasal administration, said composition comprising a therapeutically effective amount of a compound of claim 6, a pharmaceutically acceptable excipient, and water.
30. A method of administering a compound of claim 6, said method comprising intranasally administering, to a patient in need of such treatment, a therapeutically effective amount of a pharmaceutical composition containing said compound.
31. A pharmaceutical composition for intranasal administration, said composition comprising a therapeutically effective amount of a compound of claim 10, a pharmaceutically acceptable excipient, and water.
32. A method of administering a compound of claim 10, said method comprising intranasally administering, to a patient in need of such treatment, a therapeutically effective amount of a pharmaceutical composition containing said compound.
33. A pharmaceutical composition for intranasal administration, said composition comprising a therapeutically effective amount of a compound of claim 14 a pharmaceutically acceptable excipient, and water.
34. A method of administering a compound of claim 14, said method comprising intranasally administering, to a patient in need of such treatment, a therapeutically effective amount of a pharmaceutical composition containing said compound.
35. A method for the prevention or treatment of thrombosis which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of claim 6.
36. A method for the prevention or treatment of thrombosis which comprises administering to a host in need of such treatment a therapeutical effective amount of a compound of claim 10.
37. A method for the prevention or treatment of thrombosis which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of claim 11.
38. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 6 and a pharmaceutically acceptable carrier.
39. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 10 and a pharmaceutically acceptable carrier.
40. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 14 and a pharmaceutically acceptable carrier.
41. A method of inhibiting the aggregation of blood platelets which comprises administering to a host in need of such inhibition a therapeutically effective amount of a compound of claim 6.
42. A method of inhibiting the aggregation of blood platelets which comprises administering to a host in need of such inhibition a therapeutically effective amount of a compound of claim 10.
43. A method of inhibiting the aggregation of blood platelets which comprises administering to a host in need of such inhibition a therapeutically effective amount of a compound of claim 14.
44. A pharmaceutical composition for intranasal administration, said composition comprising a therapeutically effective amount of a compound of claim 6, a pharmaceutically acceptable excipient, and water.
45. A pharmaceutical composition for intranasal administration, said composition comprising a therapeutically effective amount of a compound of claim 10, a pharmaceutically acceptable excipient, and water.
46. A pharmaceutical composition for intranasal administration, said composition comprising a therapeutically effective amount of a compound of claim 14, a pharmaceutically acceptable excipient, and water.
47. A method of administering a compound of claim 6 said method comprising intranasally administering, to a patient in need of such treatment, a therapeutically effective amount of a pharmaceutical composition containing said compound.
48. A method of administering a compound of claim 10 said method comprising intranasally administering, to a patient in need of such treatment, a therapeutically effective amount of a pharmaceutical composition containing said compound.
49. A method of administering a compound of claim 19 said method comprising intranasally administering, to a patient in need of such treatment, a therapeutically effective amount of a pharmaceutical composition containing said compound.
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